Table name:

Substance	Average Duration of Effect
Anti-thyroid drugs e.g., carbimazole, propylthiouracil	5 days
Natural or synthetic thyroid hormone e.g., thyroxine tri-iodothyronine	4 weeks 2 weeks
Iodine-containing medications e.g., amiodarone expectorants, vitamins	4 weeks 2 weeks
Topical iodide	1-9 months
X-ray contrast agents iodine-containing agents	Up to 1 year
Other drugs anticoagulants, antihistamines corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium	1 week 1 week 1 week 1-2 weeks 4 weeks

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Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine^a	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir^a	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir^a, nelfinavir^a	LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir^a	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir^a	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole^a, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended.
Antimycobacterial: Rifabutin^a	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitor: Atorvastatin^a, rosuvastatin	↑Atorvastatin ↑Rosuvastatin	Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin or pravastatin.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushings syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethin-drone^a	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. ^* Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours.
Proton pump inhibitors: Esomeprazole^a, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	CmaxSS (Peak plasma concentration)	AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 4 Established and Other Potentially Significant* Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
Antiretroviral agents
Protease inhibitor: atazanavir	↓atazanavir concentration ↑ tenofovir concentration	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir concentration	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir concentration	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir concentration ↑ tenofovir concentration	A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir concentration ↑ efavirenz concentration	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir concentration	Should not be used as sole protease inhibitor in combination with ATRIPLA.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc concentration	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine concentration	Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin concentration	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine concentration ↓ efavirenz concentration	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant concentration ↓ efavirenz concentration	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion concentration	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline concentration	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole concentration ↓ hydroxy-itraconazole concentration	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole concentration	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole concentration	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin concentration ↑ 14-OH metabolite concentration	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial: rifampin	↓ efavirenz concentration	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers: diltiazem	↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone concentration	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

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Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin ^•150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

Table name:

Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Digoxin concentrations increased > 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased < 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Tolvaptan	30%	NA
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, quinine, rabeprazole,	Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine	Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which were studies but reported no significant changes on digoxin exposure.	No additional actions are required.
NA – Not available/reported

Table name:

Drugs that Affect Renal Function	Caution should be exercised when combining digoxin with any drug that may cause significant deterioration in renal function (e.g., ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors) since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

Table name: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.Coadministration of REYATAZ/ritonavir in patients on bosentan: Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.Use of REVATIO^® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ].

The following dose adjustments are recommended for the use of ADCIRCA^® (tadalafil) with REYATAZ:

Coadministration of ADCIRCA^® in patients on REYATAZ (with or without ritonavir):
For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA^®:
Avoid the use of ADCIRCA^® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA^® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Concomitant Drug Class: Specific Drugs	Effect on Concentration of Atazanavir or Concomitant Drug	Clinical Comment
^a For magnitude of interactions see Clinical Pharmacology, Tables 17 and 18 (12.3) .
^b See Contraindications (4), Table 3 for orally administered midazolam.
^c In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
^d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules	↓ atazanavir ↓ didanosine	Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate	↓ atazanavir ↑ tenofovir	Tenofovir may decrease the AUC and C_min of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz	↓ atazanavir	Efavirenz decreases atazanavir exposure. In treatment-naive patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced patients: Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
Non-nucleoside Reverse Transcriptase Inhibitors: nevirapine	↓ atazanavir ↑ nevirapine	Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure. Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors: saquinavir (soft gelatin capsules)	↑ saquinavir	Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
Protease Inhibitors: ritonavir	↑ atazanavir	If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR^® (ritonavir) for information on drug interactions with ritonavir.
Protease Inhibitors: others	↑ other protease inhibitor	REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
Other Agents
Antacids and buffered medications	↓ atazanavir	Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ amiodarone, bepridil, lidocaine (systemic), quinidine	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin	↑ warfarin	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants	↑ tricyclic antidepressants	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone	↑ trazodone	Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: ketoconazole, itraconazole	REYATAZ/ritonavir: ↑ ketoconazole ↑ itraconazole	Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C_max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
Antifungals: voriconazole	Effect is unknown	Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available.
Antigout: colchicine	↑ colchicine	REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment. Recommended dosage of colchicine when administered with REYATAZ: Treatment of gout flares:
Antimycobacterials: rifabutin	↑ rifabutin	A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolam^b	↑ midazolam	Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem	↑ diltiazem and desacetyl-diltiazem	Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
eg, felodipine, nifedipine, nicardipine, and verapamil	↑ calcium channel blocker	Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan	↓ atazanavir ↑ bosentan	Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended. Coadministration of bosentan in patients on REYATAZ/ritonavir:
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with or without ritonavir). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H₂-Receptor antagonists	↓ atazanavir	Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
		In treatment-naive patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H₂-receptor antagonist. An H₂-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H₂-receptor antagonist. No single dose of the H₂-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
		In treatment-experienced patients: Whenever an H₂-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H₂-receptor antagonist. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H₂-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H₂-receptor antagonist, see Dosage and Administration (2.3) . REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H₂-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H₂-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone	↓ ethinyl estradiol ↑ norgestimate^c ↑ ethinyl estradiol ↑ norethindrone^d	Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone	REYATAZ ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
	REYATAZ/ritonavir ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin	↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir	Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine	↑ buprenorphine ↑ norbuprenorphine	Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
		Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA^® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS^® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ/ritonavir: Use LEVITRA^® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events. REYATAZ: Use LEVITRA^® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole	↓ atazanavir	Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
		In treatment-naive patients: The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
		In treatment-experienced patients: Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 4: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Rilpivirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosineThe interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the recommended dose of EDURANT 25 mg once daily.	↔ rilpivirine ↔ didanosine	No dose adjustment is required when EDURANT is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal).
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTI (delavirdine)	↑ rilpivirine ↔ delavirdine	It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs.
Other NNRTIs (efavirenz, etravirine, nevirapine)	↓ rilpivirine ↔ other NNRTIs
HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration of low-dose ritonavir)
darunavir/ritonavir	↑ rilpivirine ↔ boosted darunavir	Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with darunavir/ritonavir.
lopinavir/ritonavir	↑ rilpivirine ↔ boosted lopinavir	Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with lopinavir/ritonavir.
other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir)	↑ rilpivirine ↔ boosted PI	Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir)	↑ rilpivirine ↔ unboosted PI	Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
Other Agents
Antacids: antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate)	↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine)	The combination of EDURANT and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT.
	↓ rilpivirine (concomitant intake)
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ rilpivirine ↓ ketoconazole	Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT.
H₂-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)	The combination of EDURANT and H₂-receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H₂-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT.
	↓ rilpivirine (famotidine taken 2 hours before rilpivirine)
Macrolide or ketolide antibiotics: clarithromycin erythromycin telithromycin	↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics: methadone	↓ R(-) methadone ↓ S(+) methadone	No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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TABLE 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug (Postulated effect on CYP450/UGT)	Dose schedules		Effect on asenapine pharmacokinetics		Recommendation
Coadministered drug (Postulated effect on CYP450/UGT)	Coadministered drug	Asenapine	C_max	AUC_0–∞
Fluvoxamine (CYP1A2 inhibitor)	25 mg twice daily for 8 days	5 mg Single Dose	+13%	+29%	Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
Paroxetine (CYP2D6 inhibitor)	20 mg once daily for 9 days	5 mg Single Dose	–13%	–9%	No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]
Imipramine (CYP1A2/2C19/3A4 inhibitor)	75 mg Single Dose	5 mg Single Dose	+17%	+10%	No SAPHRIS dose adjustment required
Cimetidine (CYP3A4/2D6/1A2 inhibitor)	800 mg twice daily for 8 days	5 mg Single Dose	–13%	+1%	No SAPHRIS dose adjustment required
Carbamazepine (CYP3A4 inducer)	400 mg twice daily for 15 days	5 mg Single Dose	–16%	–16%	No SAPHRIS dose adjustment required
Valproate (UGT1A4 inhibitor)	500 mg twice daily for 9 days	5 mg Single Dose	2%	–1%	No SAPHRIS dose adjustment required

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 7: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
^* The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
This table is not all-inclusive.
HIV antiviral agents
Protease inhibitor: Fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: Atazanavir sulfate	↓ atazanavir^*	Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.
Protease inhibitor: Indinavir	↓ indinavir^*	The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and C_min were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
Protease inhibitor: Lopinavir/ritonavir	↓ lopinavir^*	Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA.
Protease inhibitor: Ritonavir	↑ ritonavir^* ↑ efavirenz^*	When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir.
Protease inhibitor: Saquinavir	↓ saquinavir^*	Should not be used as sole protease inhibitor in combination with SUSTIVA.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs.
CCR5 co-receptor antagonist: Maraviroc	↓ maraviroc^*	Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Integrase strand transfer inhibitor: Raltegravir	↓ raltegravir^*	SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: Boceprevir	↓ boceprevir^*	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: Telaprevir	↓ telaprevir^* ↓ efavirenz^*	Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant: Warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants: Carbamazepine	↓ carbamazepine^* ↓ efavirenz^*	There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
Phenytoin Phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: Bupropion	↓ bupropion^*	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
Sertraline	↓ sertraline^*	Increases in sertraline dosage should be guided by clinical response.
Antifungals: Voriconazole	↓ voriconazole^* ↑ efavirenz^*	SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See Dosage and Administration (2.1) and Clinical Pharmacology (12.3, Tables 8 and 9) .]
Itraconazole	↓ itraconazole^* ↓ hydroxyitraconazole^*	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
Ketoconazole	↓ ketoconazole	Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.
Posaconazole	↓ posaconazole^*	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: Clarithromycin	↓ clarithromycin^* ↑ 14-OH metabolite^*	Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs , following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.
Antimycobacterials: Rifabutin	↓ rifabutin^*	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Rifampin	↓ efavirenz^*	If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.
Calcium channel blockers: Diltiazem	↓ diltiazem^* ↓ desacetyl diltiazem^* ↓ N-monodesmethyl diltiazem^*	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin	↓ atorvastatin^* ↓ pravastatin^* ↓ simvastatin^*	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate	↓ active metabolites of norgestimate^*	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant Etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immunosuppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Narcotic analgesic: Methadone	↓ methadone^*	Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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blood dyscrasias —	diarrhea	hyperthyroidism
see CONTRAINDICATIONS	elevated temperature	poor nutritional state
cancer	hepatic disorders	steatorrhea
collagen vascular disease	infectious hepatitis	vitamin K deficiency
congestive heart failure	jaundice

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Classes of Drug
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations
5-lipoxygenase Inhibitor	Antiplatelet Drugs/Effects	Leukotriene Receptor Antagonist
Adrenergic Stimulants, Central	Antithyroid Drugs^†	Monoamine Oxidase Inhibitors
Alcohol Abuse Reduction	Beta-Adrenergic Blockers	Narcotics, prolonged
Preparations	Cholelitholytic Agents	Nonsteroidal Anti-
Analgesics	Diabetes Agents, Oral	Inflammatory Agents
Anesthetics, Inhalation	Diuretics^†	Proton Pump Inhibitors
Antiandrogen	Fungal Medications,	Psychostimulants
Antiarrhythmics^†	Intravaginal, Systemic^†	Pyrazolones
Antibiotics^†	Gastric Acidity and Peptic	Salicylates
Aminoglycosides (oral)	Ulcer Agents^†	Selective Serotonin
Cephalosporins, parenteral	Gastrointestinal	Reuptake Inhibitors
Macrolides	Prokinetic Agents	Steroids, Adrenocortical^†
Miscellaneous	Ulcerative Colitis Agents	Steroids, Anabolic (17-Alkyl
Penicillins, intravenous,	Gout Treatment Agents	Testosterone Derivatives)
high dose	Hemorrheologic Agents	Thrombolytics
Quinolones (fluoroquinolones)	Hepatotoxic Drugs	Thyroid Drugs
Sulfonamides, long acting	Hyperglycemic Agents	Tuberculosis Agents^†
Tetracyclines	Hypertensive Emergency Agents	Uricosuric Agents
Anticoagulants	Hypnotics^†	Vaccines
Anticonvulsants^†	Hypolipidemics^†	Vitamins^†
Antidepressants^†	Bile Acid-Binding Resins^†
Antimalarial Agents	Fibric Acid Derivatives
Antineoplastics^†	HMG-CoA Reductase Inhibitors^†
Antiparasitic/Antimicrobials
Specific Drugs Reported
acetaminophen	fenoprofen	paroxetine
alcoholIncreased and decreased PT/INR responses have been reported.	fluconazole	penicillin G, intravenous
allopurinol	fluorouracil	pentoxifylline
aminosalicylic acid	fluoxetine	phenylbutazone
amiodarone HCl	flutamide	phenytoin
argatroban	fluvastatin	piperacillin
aspirin	fluvoxamine	piroxicam
atenolol	gefitinib	pravastatin
atorvastatin	gemfibrozil	prednisone
azithromycin	glucagon	propafenone
bivalirudin	halothane	propoxyphene
capecitabine	heparin	propranolol
cefamandole	ibuprofen	propylthiouracil
cefazolin	ifosfamide	quinidine
cefoperazone	indomethacin	quinine
cefotetan	influenza virus vaccine	rabeprazole
cefoxitin	itraconazole	ranitidine
ceftriaxone	ketoprofen	rofecoxib
celecoxib	ketorolac	sertraline
cerivastatin	lansoprazole	simvastatin
chenodiol	lepirudin	stanozolol
chloramphenicol	levamisole	streptokinase
chloral hydrate	levofloxacin	sulfamethizole
chlorpropamide	levothyroxine	sulfamethoxazole
cholestyramine	liothyronine	sulfinpyrazone
cimetidine	lovastatin	sulfisoxazole
ciprofloxacin	mefenamic acid	sulindac
cisapride	methimazole	tamoxifen
clarithromycin	methyldopa	tetracycline
clofibrate	methylphenidate	thyroid
warfarin sodium overdose	methylsalicylate ointment (topical)	ticarcillin
cyclophosphamide	metronidazole	ticlopidine
danazol	miconazole	tissue plasminogen
dextran	(intravaginal, oral, systemic)	activator (t-PA)
dextrothyroxine	moricizine hydrochloride	tolbutamide
diazoxide	nalidixic acid	tramadol
diclofenac	naproxen	trimethoprim/sulfamethoxazole
dicumarol	neomycin	urokinase
diflunisal	norfloxacin	valdecoxib
disulfiram	ofloxacin	valproate
doxycycline	olsalazine	vitamin E
erythromycin	omeprazole	zafirlukast
esomeprazole	oxandrolone	zileuton
ethacrynic acid	oxaprozin
ezetimibe	oxymetholone
fenofibrate	pantoprazole

Table name:

edema	hypothyroidism
hereditary coumarin resistance	nephrotic syndrome
hyperlipemia

Table name:

Classes of Drugs
also: diet high in vitamin K unreliable PT/INR determinations
Adrenal Cortical Steroid Inhibitors	Antipsychotic Medications	Hypolipidemics^†
Antacids	Antithyroid Drugs^†	Bile Acid-Binding Resins^†
Antianxiety Agents Antiarrhythmics^†	Barbiturates Diuretics^†	HMG-CoA Reductase Inhibitors^†
Anticonvulsants^†	Enteral Nutritional Supplements	Immunosuppressives
Antidepressants^†	Fungal Medications, Systemic^†	Oral Contraceptives,
Antihistamines	Gastric Acidity and Peptic Ulcer Agents^†	Estrogen Containing
Antineoplastics^†	Hypnotics^†	Selective Estrogen Receptor Modulators
		Steroids, Adrenocortical^†
		Tuberculosis Agents^† Vitamins^†
Specific Drugs Reported:
alcoholIncreased and decreased PT/INR responses have been reported.	warfarin sodium underdosage	phenytoin
aminoglutethimide	cyclophosphamide	pravastatin
amobarbital	dicloxacillin	prednisone
atorvastatin	ethchlorvynol	primidone
azathioprine	glutethimide	propylthiouracil
butabarbital	griseofulvin	raloxifene
butalbital	haloperidol	ranitidine
carbamazepine	meprobamate	rifampin
chloral hydrate	6-mercaptopurine	secobarbital
chlordiazepoxide	methimazole	spironolactone
chlorthalidone	moricizine hydrochloride	sucralfate
cholestyramine	nafcillin	trazodone
clozapine	paraldehyde	vitamin C (high dose)
corticotropin	pentobarbital	vitamin K
cortisone	phenobarbital

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary digestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
Antiretroviral agents
Protease inhibitor: atazanavir	↓atazanavir concentration ↑ tenofovir concentration	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir concentration	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir concentration	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir concentration ↑ tenofovir concentration	A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir concentration ↑ efavirenz concentration	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir concentration	Should not be used as sole protease inhibitor in combination with ATRIPLA.
NRTI: didanosine	↑ didanosine concentration	Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin concentration	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine concentration ↓ efavirenz concentration	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant concentration ↓ efavirenz concentration	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant: sertraline	↓ sertraline concentration	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole concentration ↓ hydroxy-itraconazole concentration	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole concentration	Drug interaction studies with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
Anti-infective: clarithromycin	↓ clarithromycin concentration ↑ 14-OH metabolite concentration	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial: rifampin	↓ efavirenz concentration	Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established.
Calcium channel blockers: diltiazem	↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration	Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: Ethinyl estradiol/Norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: Etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone concentration	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 4 Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug name	Effect on Concentration of Tipranavir or Concomitant Drug	Clinical Comment
↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict
HIV-1 Antiviral Agents
Fusion Inhibitors:
Enfuvirtide	↑ Tipranavir	At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended.
Nucleoside Reverse Transcriptase Inhibitors:
Abacavir	↓ Abacavir AUC by approximately 40%	Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.

Didanosine (EC)	↓ Didanosine	Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS/ritonavir dosing by at least 2 hours.

Zidovudine	↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered.	Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.
Protease Inhibitors (co-administered with 200 mg of ritonavir):
Fosamprenavir Lopinavir Saquinavir	↓ Amprenavir ↓ Lopinavir ↓ Saquinavir	Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.
Protease Inhibitors (co-administered with 100 mg of ritonavir):
Atazanavir	↓ Atazanavir ↑ Tipranavir
Virus Integrase Strand Transfer Inhibitors:
Raltegravir	↓ Raltegravir	APTIVUS/ritonavir reduces plasma concentrations of raltegravir. Since comparable efficacy was observed for this combination in phase 3 studies, dose adjustment is not recommended.
Agents for Opportunistic Infections
Antifungals:
Fluconazole	↑ Tipranavir, ↔ Fluconazole	Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended.

Itraconazole Ketoconazole	↑ Itraconazole (not studied) ↑ Ketoconazole (not studied)	Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (>200 mg/day) are not recommended.

Voriconazole	↕ Voriconazole (not studied)	Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction.
Antimycobacterials:
Clarithromycin	↑ Tipranavir, ↑ Clarithromycin, ↓ 14-hydroxy-clarithromycin metabolite	No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary.
		For patients with renal impairment the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%.

Rifabutin	Tipranavir not changed, ↑ Rifabutin ↑ Desacetyl-rifabutin	Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g., 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage reduction may be necessary.
Other Agents Commonly Used
Anticonvulsants:
Carbamazepine Phenobarbital Phenytoin	↓ Tipranavir	Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly.

Valproic Acid	↓ Valproic Acid	Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking APTIVUS concomitantly.
Antidepressants: Trazodone	↑ Trazodone	Concomitant use of trazodone and APTIVUS/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

Desipramine	Combination with APTIVUS/ritonavir not studied ↑ Desipramine	Dosage reduction and concentration monitoring of desipramine is recommended.

Selective Serotonin-Reuptake Inhibitors:	Combination with APTIVUS/ritonavir not studied	Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.
Fluoxetine Paroxetine Sertraline	↑ Fluoxetine ↑ Paroxetine ↑ Sertraline
Anti-gout Colchicine	↑ Colchicine	Patients with renal or hepatic impairment should not be given colchicine with APTIVUS/ritonavir. Treatment of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir : If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Co-administration of colchicine in patients on APTIVUS/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Benzodiazepines:
Parenterally administered midazolam	↑ Midazolam	Midazolam is extensively metabolized by CYP 3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, APTIVUS should not be given with orally administered midazolam [ see Contraindications (4) ]. If APTIVUS is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustments should be considered.
Buprenorphine/naloxone	↔ Buprenorphine ↓ Tipranavir	APTIVUS/ritonavir did not result in changes in the clinical efficacy of buprenorphine/naloxone. Compared to historical controls tipranavir C_min was decreased approximately 40% with this combination. Dose adjustments cannot be recommended.
Calcium Channel Blockers: Diltiazem Felodipine Nicardipine Nisoldipine Verapamil	Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP3A and P-gp due to conflicting effect of TPV/ritonavir on CYP3A and P-gp. ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil	Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/Metronidazole	Combination with TPV/ritonavir not studied	APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists		Co-administration of bosentan in patients on APTIVUS/ritonavir:
Bosentan	↑ Bosentan	In patients who have been receiving APTIVUS/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of APTIVUS/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of APTIVUS/ritonavir. After at least 10 days following the initiation of APTIVUS/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
Atorvastatin Rosuvastatin	↑ Atorvastatin ↓ Hydroxy-atorvastatin metabolites ↑ Rosuvastatin	Avoid co-administration with atorvastatin.
Hypoglycemics:
	Combination with APTIVUS/ritonavir not studied	Careful glucose monitoring is warranted.

Glimepiride Glipizide Glyburide Pioglitazone	↔ Glimepiride (CYP 2C9) ↔ Glipizide (CYP 2C9) ↔ Glyburide (CYP 2C9) ↕ Pioglitazone (CYP 2C8 and CYP 3A4)
Repaglinide	↕ Repaglinide (CYP 2C8 and CYP 3A4)
Tolbutamide	↔ Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8 substrate is not known.
Immunosuppressants:
	Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp.	Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended.
Cyclosporine Sirolimus Tacrolimus	↕ Cyclosporine ↕ Sirolimus ↕ Tacrolimus
Inhaled beta agonist: Salmeterol	↑ Salmeterol	Concurrent administration of APTIVUS/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/Nasal Steroids:
Fluticasone	↑ Fluticasone	Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic Analgesics:
Meperidine	Combinations with APTIVUS/ritonavir not studied ↓ Meperidine, ↑ Normeperidine	Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).

Methadone	↓ Methadone ↓ S-Methadone, ↓ R-Methadone	Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir.

Oral Contraceptives/Estrogens:
Ethinyl estradiol	↓ Ethinyl estradiol concentrations by 50%	Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with APTIVUS and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non-serious rash.
Proton Pump Inhibitors:
Omeprazole	↓ Omeprazole, ↔ Tipranavir	Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir.
PDE-5 Inhibitors:
	Only the combination of tadalafil with APTIVUS/ritonavir has been studied (at doses used for treatment of erectile dysfunction).	Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Sildenafil	↑ Sildenafil (not studied)	Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4.2)]. The following dose adjustments are recommended for use of tadalafil (Adcirca) with APTIVUS/ritonavir:
Tadalafil	↑ Tadalafil with first dose APTIVUS/ritonavir ↔ Tadalafil at APTIVUS/ritonavir steady-state	Co-administration of tadalafil (Adcirca) in patients on APTIVUS/ritonavir: In patients receiving APTIVUS/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Vardenafil	↑ Vardenafil (not studied)	Co-administration of APTIVUS/ritonavir in patients on tadalafil (Adcirca): Avoid use of tadalafil (Adcirca) during the initiation of APTIVUS/ritonavir. Stop Adcirca at least 24 hours prior to starting APTIVUS/ritonavir. After at least one week following the initiation of APTIVUS/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Concomitant use of PDE-5 inhibitors with APTIVUS/ritonavir should be used with caution and in no case should the starting dose of: sildenafil exceed 25 mg within 48 hours tadalafil exceed 10 mg every 72 hours vardenafil exceed 2.5 mg every 72 hours Use with increased monitoring for adverse events.
Warfarin	↔ S-Warfarin	Frequent INR (international normalized ratio) monitoring upon initiation of APTIVUS/ritonavir therapy.

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine × 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole

	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ

Low-dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

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Table 1. Selected Drugs That Have Been Shown To or Are Predicted To Have Their Plasma Concentrations Altered By NIZORAL^® This list is not all-inclusive.
Systemic exposure to these drugs is increased significantly by the addition of ketoconazole: Concomitant use with ketoconazole is contraindicated.
Alprazolam, midazolam, triazolam	HMG-CoA reductase inhibitors (lovastatin, simvastatin)
Cisapride	Nisoldipine
Dofetilide	Pimozide
Eplerenone	Quinidine
Ergot alkaloids (ergotamine, dihydroergotamine)
Systemic exposure to these drugs is increased by ketoconazole: Careful monitoring, with possible adjustment in dosage, is recommended.
Alfentanil, fentanyl, sulfentanil	Indinavir, saquinavir
Amlodipine, felodipine, nicardipine, nifedipine	Methylprednisolone
Bosentan	Rifabutin
Buspirone	Sildenafil
Busulfan	Sirolimus (co-administration not recommended)
Carbamazepine	Tacrolimus
Cilostazol	Telithromycin
Cyclosporine	Tolterodine
Digoxin	Trimetrexate
Docetaxel, paclitaxel	Verapamil
Oral anti-coagulants	Vinca alkaloids (vincristine, - vinblastine, vinorelbine)

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Table 2. Selected Drugs That Have Been Shown To or Are Predicted To Alter The Plasma Concentration Of NIZORAL^®
Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended.
* This list is not all-inclusive.
Carbamazepine	Phenytoin
Gastric Acid Suppressants (antacids, antimuscarinics, histamine H_2-blockers, proton pump inhibitors, sucralfate)	Rifampin, rifabutin, isoniazid
Nevirapine
Systemic exposure to ketoconazole is increased significantly by this drug: Dose reduction of ketoconazole should be considered
Ritonavir

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albuterol, systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin, with or without	methylprednisolone
sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine
cefaclor	nizatidine
co-trimoxazole (trimethoprim and sulfamethoxazole)	norfloxacin
co-trimoxazole (trimethoprim and sulfamethoxazole)	ofloxacin
diltiazem	omeprazole
dirithromycin	prednisone, prednisolone
enflurane	ranitidine
famotidine	rifabutin
felodipine	roxithromycin
finasteride	Sorbitol (purgative doses do not inhibit
hydrocortisone	theophylline absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide
lomefloxacin

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Table 3: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values^a
Drug	Didanosine Dosage	n	AUC of Didanosine (90% CI)	Cmax of Didanosine (90% CI)
tenofovir,^b 300 mg once daily with a light meal^c	400 mg single dose fasting 2 h before tenofovir	26	↑ 48% (31, 67%)	↑ 48% (25, 76%)
tenofovir,^b 300 mg once daily with a light meal^c	400 mg single dose with tenofovir and a light meal	25	↑ 60% (44, 79%)	↑ 64% (41, 89%)
tenofovir,^b 300 mg once daily with a light meal^c	200 mg single dose with tenofovir and a light meal 250 mg single dose with tenogovir and a light meal 325 mg single dose with tenofovir and a light meal	33 33 33	↑ 16% (6, 27%)^d ↔(-13, 5%)^e ↑ 13% (3, 24%)	↓ 12% (-25, 3%)^d ↓ 20% (-32, -7%)^e ↓ 11% (-24, 4%)^e
↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. ^a All studies conducted in healthy volunteers ≥60kg with creatinine clearance ≥60 mL/min. ^b tenofovir disporoxil fumarate. ^c 373 kcalories, 8.2 grams fat. ^d Compared with didanosine delayed-release capsules 250 mg administered alone under fasting coniditions. ^e Compared with didanosine delayed-release capsules 400 mg administered alone under fasting conditions.

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Table 4: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values^a
↔ Indicates no change, or mean increase or decrease of less than 10%.
* The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed. † All studies conducted in healthy volunteers ≥ 60 kg with creatinine clearance ≥ 60 mL/min. ‡ Tenofovir disoproxil fumarate. § 373 kcalories, 8.2 grams fat.
Drug	Didanosine Dosage	n	AUC of Coadministered Drug	Cmax of Coadministered Drug
ciprofloxacin, 750 mg single dose indinavir, 800 mg single dose ketoconazole, 200 mg single dose tenofovir,‡ 300 mg once daily with a light meal§ tenofovir,‡ 300 mg once daily with a light meal§	400 mg single dose 400 mg single dose 400 mg single dose 400 mg single dose fasting 2h before tenofovir 400 mg single dose with tenofovir anda light meal	16 23 21 25 25	↔ ↔ ↔ ↔ ↔	↔ ↔ ↔ ↔ ↔

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Table 5: Results of Drug Interaction Studies with Buggered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine plasma AUC and Cmax Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS, Drug Interactions )
Drug	Didanosine Dosage	n	AUC Didanosine (95% CI)	Cmax of Didanosine (95% CI)
allopurinol, Renally impaired, 300 mg/day	200 mg single dose	2	↑312%	↑232%
healthy volunteer, 300 mg/day for 7 days	400 mg single dose	14	↑113%	↑69%
ganciclovir, 1000 mg q8h, 2 h after didanosine	200 mg q12h	12	↑111%	NA
methadone, chronic maintenance dose	200 mg single dose	16, 10^a	↓57%	↓66%
tenofovir,^b 300 mg once daily 1 h after didanosine	250^c or 400 mg once daily for 7 days	14	↑44% (31, 59%)^d	↔28% (11, 48%)^d
No Clinically Significant Interactions Observed
ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine	200 mg q12h for 3 days	8^e	↓16%	↓28%
ininavir, 800 mg single dose simultaneous	200 mg single dose	16	↔	↔
1 h before didanosine	200 mg single dose	16	↓17% (-27, -7%)^d	↓13% (-28, 5%)^d
ketoconazole, 200 mg/day for 4 days, 2 h before didanosine	375 mg q12h for 4 days	12^e	↔	↓12%
loperamide, 4 mg q6h for 1 day	300 mg single dose	12^e	↔	↓23%
metoclopramide, 10 mg single dose	300 mg single dose	12^e	↔	↑13%
ranitidine, 150 mg 2 h before didansine	375 mg single dose	12^e	↑14%	↑13%
rifabutin, 300 or 600 mg/day for 12 days	167 or 250 mg q12h for 12 days	11	↑13% (-1, 27%)	↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days	200 mg q12h for 4 days	12	↓13% (0, 23%)	↓16% (5, 26%)
stavudine, 40 mg q12h for 4 days	100 mg q12h for 4 days	10	↔	↔
sulfamethoxazole, 1000 mg single dose	200 mg single dose	8^e	↔	↔
trimethoprim, 200 mg single dose	200 mg single dose	8^e	↔	↑17% (-23, 77%)
zidovudine, 200 mg q7h for 3 days	200 mg q12h for 3 days	8^e	↔	↔
↑ indicates increase ↓ indicates decrease ↔ indicates no change, or mean increase or decrease of <10%. ^a Parellel-group design; entries are subjects receiving combination and control regimens, respectively. ^b tenogovir disoproxil fumarate ^c patients <60 kg with creatinine clearance >60 mL/min. ^d 90% CI ^e HIV-infected patients N/A Not available

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Table 6: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
No Clinically Significant Interaction Observed
Drug	Didanosine Dosage	n	AUC of Coadministered Drug (95% CI)	Cmax of Coadministered Drug (95% CI)
dapsone, 100 mg single dose	200 mg q12h for 14 days	6^a	↔	↔
delaviridine, 400 mg single dose simultaneous	125 or 200 mg q12h	12^a	↓32%^b	↓53%^b
1 hr before didanosine	125 or 200 mg q12h	12^a	↑20%	↑18%
ganciclovir, 1000 mg q8h, 2h after didanosine	200 mg q12h	12^a	↓21%	NA
nelfinavir, 750 mg single dose, 1 h after didanosine	200 mg single dose	10^a	↑12%	↔
ranitidine, 150 mg single dose, 2 h before didanosine	375 mg single dose	12^a	↓16%	↔
ritonavir, 600 mg q12h for 4 days	200 mg q12h for 4 days	12	↔	↔
stavudine, 40 mg q12h for 4 days	100 mg q12h for 4 days	10^a	↔	↑17%
sulfamethoxazole, 1000 mg single dose	200 mg single dose	8^a	↓11% (-17, -4%)	↓12% (-28, 8%)
tenofovir,^C 300 mg once daily 1 h after didanosine	250^d or 400 mg once daily for 7 days	14	↔	↔
trimethoprim, 200 mg single dose	200 mg single dose	8^a	↑10% (-9, 34%)	↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3 days	200 mg q12h for 3 days	6^a	↓10% (-27, 11%)	↓16.5% (-53, 47%)
↑ indicates increase. ↓indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. ^aHIV-infected patients. ^bThis result is probably related to the bugger and is not expected to occur with didanosine delayed-release capsules. ^ctenofovir disoproxil fumarate. ^dpatients <60 kg with creatinine clearance >60 mL/min.NA Not available

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine	↓ Efavirenz	Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be decreased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be increased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Table 3 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class: Drug Name	Effect on Concentration of Saquinavir or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Delavirdine*	↑ Saquinavir Effect on delavirdine is not well established	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz†, nevirapine	↓ Saquinavir ↔ Efavirenz	Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor: Atazanavir	INVIRASE/ritonavir ↑ Saquinavir ↑ Ritonavir ↔ Atazanavir	Atazanavir in combination with INVIRASE/ritonavir should be used with caution. Additive effects on PR interval prolongation may occur with INVIRASE/ritonavir [see Warnings and Precautions (5.2)].
HIV-1 protease inhibitor: Indinavir	↑ Saquinavir Effect on indinavir is not well established	Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor: Lopinavir/ritonavir (coformulated tablet)	↔ Saquinavir ↔ Lopinavir ↓ Ritonavir	Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid. Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.2, 5.3)].
HIV-1 protease inhibitor: Tipranavir/ritonavir	↓ Saquinavir	Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV-1 fusion inhibitor: Enfuvirtide	Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide	No clinically significant interaction was noted from a study in 12 HIV-1 subjects who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
HIV-1 CCR5 antagonist: Maraviroc	↑ Maraviroc	Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Ibutilide Sotalol		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Anticoagulant: Warfarin	↑ Warfarin	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin	↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established	Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-gout: Colchicine	↑ Colchicine	Treatment of gout flares-coadministration of colchicine in patients on INVIRASE/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Treatment of familial Mediterranean fever (FMF) coadministration of colchicine in patients on INVIRASE/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Prophylaxis of gout-flares-co-administration of colchicine in patients on INVIRASE/ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir.
Anti-infective: Clarithromycin	↑ Saquinavir ↑ Clarithromycin	Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Erythromycin Halofantrine Pentamidine		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Antifungal: Ketoconazole, itraconazole	↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole	When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see Table 3 ). Hence, doses of ketoconazole or itraconazole >200 mg/day are not recommended.
Antimycobacterial: Rifabutin	↔ Saquinavir ↑ Rifabutin ↔ Ritonavir	No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if ritonavir-boosted INVIRASE is administered in combination with rifabutin. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination. Consider monitoring rifabutin concentrations to ensure adequate exposure.
Benzodiazepines : Alprazolam, clorazepate, diazepam, flurazepam	↑ Benzodiazepines	Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine : Intravenously administered Midazolam	↑ Midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see Contraindications (4)]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers : Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑ Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓ Saquinavir	Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations.
Digitalis Glycosides: Digoxin	↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.	Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir.
Endothelin receptor antagonists: Bosentan	↑ Bosentan	Coadministration of bosentan in patients on INVIRASE/ritonavir: In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of INVIRASE/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir. After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Inhaled beta agonist: Salmeterol	↑ Salmeterol	Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	INVIRASE/ritonavir ↑ Fluticasone	Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
HMG-CoA reductase inhibitors : Atorvastatin	↑ Atorvastatin	Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day.
Immunosuppressants : Cyclosporine, tacrolimus, rapamycin	↑ Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic: Methadone	↓ Methadone	Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Neuroleptics: Clozapine Haloperidol Mesoridazine Phenothiazines Thioridazine Ziprasidone		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Oral contraceptives: Ethinyl estradiol	↓ Ethinyl estradiol	Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors): Sildenafil, vardenafil, tadalafil	↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction.	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with INVIRASE/ritonavir: Coadministration of Adcirca in patients on INVIRASE/ritonavir: In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of INVIRASE/ritonavir in patients on Adcirca: Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Tricyclic antidepressants : Amitriptyline, imipramine	↑ Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Proton pump inhibitors: Omeprazole	↑ Saquinavir	When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.
Herbal Products: St. John's wort (hypericum perforatum)	↓ Saquinavir	Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
Garlic Capsules	↓ Saquinavir	Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone),gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 6: Summary of drug-drug interactions of BANZEL with other antiepileptic drugs
^a) Predictions are based on BANZEL concentrations at the maximum recommended dose of BANZEL. ^b) Maximum changes predicted to be in children and in patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent. ^c) Larger effects in children at high doses/concentrations of AEDs. ^d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on BANZEL clearance. ^e) All compounds of the benzodiazepine class were pooled to examine for 'class effect' on BANZEL clearance.
AED Co-administered	Influence of Rufinamide on AED concentration^a)	Influence of AED on Rufinamide concentration
Carbamazepine	Decrease by 7 to 13%^b)	Decrease by 19 to 26% Dependent on dose of carbamazepine
Lamotrigine	Decrease by 7 to 13%^b)	No Effect
Phenobarbital	Increase by 8 to 13%^b)	Decrease by 25 to 46% ^c), d) Independent of dose or concentration of Phenobarbital
Phenytoin	Increase by 7 to 21%^b)	Decrease by 25 to 46% ^c), d) Independent of dose or concentration of phenytoin
Topiramate	No Effect	No Effect
Valproate	No Effect	Increase by <16 to 70% ^c) Dependent on concentration of valproate
Primidone	Not Investigated	Decrease by 25 to 46% ^c), d) Independent of dose or concentration of primidone
Benzodiazepines^e)	Not Investigated	No Effect

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for Magnitude of Interaction.

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate capsules, USP prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , ) 2.6 5.1 7.1 7.2 7.3 7.4
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 5. Significant Interactions Between POTIGA and Concomitant Antiepileptic Drugs
AED	Dose of AED (mg/day)	Dose of POTIGA (mg/day)	Influence of POTIGA on AED	Influence of AED on POTIGA	Dosage Adjustment
Carbamazepine^a,b	600-2,400	300-1,200	None	31% decrease in AUC, 23% decrease in C_max	consider an increase in dosage of POTIGA when adding carbamazepine^c
Phenytoin^a,b	120-600	300-1,200	None	34% decrease in AUC, 18% decrease in C_max	consider an increase in dosage of POTIGA when adding phenytoin^c

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule	Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)	Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
* Change relative to reference

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration		Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen		Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole

	% Change from Plavix (300 mg/75 mg) alone
Plavix plus	C_max (ng/mL)		AUC		Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
	Day 1	Day 5	Day 1	Day 5AUC at Day 5 is AUC_0–24	Day 1	Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg	↓46%	↓42%	↓45%	↓40%	↓39%	↓21%
Pantoprazole 80 mg	↓24%	↓28%	↓20%	↓14%	↓15%	↓11%

Table name:

CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
Opioids	Cross-tolerance and mutual potentiation
Naltrexone	Oral THC effects were enhanced by opioid receptor blockade.
Alcohol	Increase in the positive subjective mood effects of smoked marijuana

Table name:

Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUCss_(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

Table name:

Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration		Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen		Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Table 9: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 12 and 13]
Concomitant Drug Class: Drug Name	Effect on Concentration of Darunavir or Concomitant Drug	Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine	↔ darunavir ↔ didanosine	Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)	↑ darunavir ↑ indinavir	The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir	↓ darunavir ↔ lopinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir	↓ darunavir ↔ saquinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc	↑ maraviroc	Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics: bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone	↑ antiarrhythmics	Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin	↑ digoxin	The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant: warfarin	↓ warfarin ↔ darunavir	Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant: carbamazepine	↔ darunavir ↑ carbamazepine	The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant: phenobarbital, phenytoin	↔ darunavir ↓ phenytoin ↓ phenobarbital	Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant: trazodone, desipramine	↑ trazodone ↑ desipramine	Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective: clarithromycin	↔ darunavir ↑ clarithromycin	No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals: ketoconazole, itraconazole, voriconazole	↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied)	Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
		Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
		Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimycobacterial: rifabutin	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin	Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel Blockers: felodipine, nifedipine, nicardipine	↑ calcium channel blockers	Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Systemic: dexamethasone	↓ darunavir	Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents: NS3-4A protease inhibitors: boceprevir telaprevir	↓ darunavir ↓ boceprevir ↓ telaprevir	Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin	↑ pravastatin ↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence: methadone, buprenorphine, buprenorphine/naloxone	↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite)	No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics: risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone	↓ ethinyl estradiol ↓ norethindrone	Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors: sildenafil, vardenafil, tadalafil	↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir)	Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine	↔ darunavir ↓ sertraline ↓ paroxetine	If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 4. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Ritonavir or Concomitant Drug	Clinical Comments
		HIV-Antiviral Agents
HIV-1 Protease Inhibitor: atazanavir	When co-administered with reduced doses of atazanavir and ritonavir ↑ atazanavir (↑ AUC, ↑ C_max, ↑ C_min)	Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. See the complete prescribing information for Reyataz^® (atazanavir) for details on co-administration of atazanavir 300 mg once daily with ritonavir 100 mg once daily.
HIV-1 Protease Inhibitor: darunavir	When co-administered with reduced doses of ritonavir ↑ darunavir (↑ AUC, ↑ C_max, ↑ C_min)	See the complete prescribing information for Prezista^® (darunavir) for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily or darunavir 800 mg once daily with ritonavir 100 mg once daily.
HIV-1 Protease Inhibitor: fosamprenavir	When co-administered with reduced doses of ritonavir ↑ amprenavir (↑ AUC, ↑ C_max, ↑ C_min)	See the complete prescribing information for Lexiva^® (fosamprenavir) for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily or fosamprenavir 1400 mg once daily with ritonavir 100 mg once daily.
HIV-1 Protease Inhibitor: indinavir	When co-administered with reduced doses of indinavir and ritonavir ↑ indinavir (↔ AUC, ↓ C_max, ↑ C_min)	Alterations in concentrations are noted when reduced doses of indinavir are co-administered with NORVIR. Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV-1 Protease Inhibitor: saquinavir	When co-administered with reduced doses of ritonavir ↑ saquinavir (↑ AUC, ↑ C_max, ↑ C_min)	See the complete prescribing information for Invirase^® (saquinavir) for details on co-administration of saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily. Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV-1 Protease Inhibitor: tipranavir	When co-administered with reduced doses of ritonavir ↑ tipranavir (↑ AUC, ↑ C_max, ↑ C_min)	See the complete prescribing information for Aptivus^® (tipranavir) for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.
Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ ritonavir (↑AUC, ↑C_max, ↑ C_min)	Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV-1 CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry^® (maraviroc).
Integrase Inhibitor: Raltegravir	↓ raltegravir	The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic: tramadol, propoxyphene		A dose decrease may be needed for these drugs when co-administered with ritonavir.
Anesthetic: meperidine	↓ meperidine/ ↑ normeperidine (metabolite)	Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics: disulfiram/metronidazole		Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics: disopyramide, lidocaine, mexiletine	↑antiarrhythmics	Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents: dasatinib, nilotinib, vincristine, vinblastine	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin	↓ R-warfarin ↓↑ S-warfarin	Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is indicated.
Anticoagulant: rivaroxaban	↑ rivaroxaban	Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, clonazepam, ethosuximide	↑anticonvulsants	Use with caution. A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants: divalproex, lamotrigine, phenytoin	↓anticonvulsants	Use with caution. A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline	↑antidepressants	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: desipramine	↑ desipramine	Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiemetic: dronabinol	↑ dronabinol	A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungal: ketoconazole itraconazole voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with ritonavir. Treatment of gout flares-co-administration of colchicine in patients on ritonavir: 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days. Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial: rifabutin	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial: rifampin	↓ ritonavir	May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations).
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic: quinine	↑ quinine	A dose decrease of quinine may be needed when co-administered with ritonavir.
β-Blockers: metoprolol, timolol	↑ Beta-Blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator: theophylline	↓ theophylline	Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers: diltiazem, nifedipine, verapamil	↑ calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin	↑ digoxin	Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on ritonavir: In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability Co-administration of ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin)	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Inhaled or Intranasal Steroid: e.g. fluticasone budesonide	↑ glucocorticoids	Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone fentanyl	↓ methadone ↑ fentanyl	Dosage increase of methadone may be considered. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Neuroleptics: perphenazine, risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Oral Contraceptives or Patch Contraceptives: ethinyl estradiol	↓ ethinyl estradiol	Alternate methods of contraception should be considered.
PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil (Adcirca^TM) with ritonavir: Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours. Use with increased monitoring for adverse events.
Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem	↑ sedative/hypnotics	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics: Parenteral midazolam	↑ midazolam	Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Steroids (systemic): e.g. budesonide dexamethasone, prednisone	↑ glucocorticoids	Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Stimulant: methamphetamine	↑ methamphetamine	Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_max SS (Peak plasma concentration)	AUC_SS(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:
0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.Prophylaxis of gout flares:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF):
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.Coadministration of REYATAZ/ritonavir in patients on bosentan:
Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Use of REVATIO^® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ].

The following dose adjustments are recommended for the use of ADCIRCA^® (tadalafil) with REYATAZ:

Coadministration of ADCIRCA^® in patients on REYATAZ (with or without ritonavir):
For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA^®:
Avoid the use of ADCIRCA^® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA^® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Concomitant Drug Class: Specific Drugs	Effect on Concentration of Atazanavir or Concomitant Drug	Clinical Comment
^a For magnitude of interactions see Clinical Pharmacology, Tables 17 and 18 (12.3) .
^b See Contraindications (4), Table 3 for orally administered midazolam.
^c In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
^d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules	↓ atazanavir ↓ didanosine	Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate	↓ atazanavir ↑ tenofovir	Tenofovir may decrease the AUC and C_min of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz	↓ atazanavir	Efavirenz decreases atazanavir exposure. In treatment-naive patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced patients: Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
nevirapine	↓ atazanavir ↑ nevirapine	Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure. Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors: saquinavir (soft gelatin capsules)	↑ saquinavir	Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
ritonavir	↑ atazanavir	If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR^® (ritonavir) for information on drug interactions with ritonavir.
others	↑ other protease inhibitor	REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
HCV Antiviral Agents
Protease Inhibitors: boceprevir	↓ atazanavir ↓ ritonavir	Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of REYATAZ/ritonavir and boceprevir is not recommended.
telaprevir	↓ telaprevir ↑ atazanavir	Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
Other Agents
Antacids and buffered medications	↓ atazanavir	Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ amiodarone, bepridil, lidocaine (systemic), quinidine	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin	↑ warfarin	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants	↑ tricyclic antidepressants	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone	↑ trazodone	Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiepileptics: carbamazepine	↓ atazanavir ↑ carbamazepine	Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with REYATAZ/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary.
phenytoin, phenobarbital	↓ atazanavir ↓ phenytoin ↓ phenobarbital	Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with REYATAZ without ritonavir. Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.
lamotrigine	↓ lamotrigine	Coadministration of lamotrigine and REYATAZ with ritonavir may decrease lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be required when coadministered with REYATAZ and ritonavir. Coadministration of lamotrigine and REYATAZ without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals: ketoconazole, itraconazole	REYATAZ/ritonavir: ↑ ketoconazole ↑ itraconazole	Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C_max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
voriconazole	REYATAZ/ritonavir in subjects with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ/ritonavir in subjects without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir	Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse events and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.
Antigout: colchicine	↑ colchicine	REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment. Recommended dosage of colchicine when administered with REYATAZ: Treatment of gout flares:
Antimycobacterials: rifabutin	↑ rifabutin	A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolam^b	↑ midazolam	Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem	↑ diltiazem and desacetyl-diltiazem	Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
felodipine, nifedipine, nicardipine, and verapamil	↑ calcium channel blocker	Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan	↓ atazanavir ↑ bosentan	Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended. Coadministration of bosentan in patients on REYATAZ/ritonavir:
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H₂-Receptor antagonists	↓ atazanavir	Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
		In treatment-naive patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H₂-receptor antagonist. An H₂-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H₂-receptor antagonist. No single dose of the H₂-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
		In treatment-experienced patients: Whenever an H₂-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H₂-receptor antagonist. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H₂-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H₂-receptor antagonist, see Dosage and Administration (2.3) . REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H₂-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H₂-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone	↓ ethinyl estradiol ↑ norgestimate^c	Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
	↑ ethinyl estradiol ↑ norethindrone^d	Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone	REYATAZ ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
	REYATAZ/ritonavir ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin	↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir	Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine	↑ buprenorphine ↑ norbuprenorphine	Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
		Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA^® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS^® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ/ritonavir: Use LEVITRA^® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events. REYATAZ: Use LEVITRA^® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole	↓ atazanavir	Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
		In treatment-naive patients: The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
		In treatment-experienced patients: Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug (Postulated effect on CYP450/UGT)	Dose schedules		Effect on asenapine pharmacokinetics		Recommendation
Coadministered drug (Postulated effect on CYP450/UGT)	Coadministered drug	Asenapine	C_max	AUC_0-∞
Fluvoxamine (CYP1A2 inhibitor)	25 mg twice daily for 8 days	5-mg Single Dose	+13%	+29%	Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
Paroxetine (CYP2D6 inhibitor)	20 mg once daily for 9 days	5-mg Single Dose	–13%	–9%	No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]
Imipramine (CYP1A2/2C19/3A4 inhibitor)	75-mg Single Dose	5-mg Single Dose	+17%	+10%	No SAPHRIS dose adjustment required
Cimetidine (CYP3A4/2D6/1A2 inhibitor)	800 mg twice daily for 8 days	5-mg Single Dose	–13%	+1%	No SAPHRIS dose adjustment required
Carbamazepine (CYP3A4 inducer)	400 mg twice daily for 15 days	5-mg Single Dose	–16%	–16%	No SAPHRIS dose adjustment required
Valproate (UGT1A4 inhibitor)	500 mg twice daily for 9 days	5-mg Single Dose	2%	–1%	No SAPHRIS dose adjustment required

Table name:

Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary digestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cation or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agent	Carefully monitor blood glucose (5.11, 7.3)

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE^® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. nevirapine	↓ etravirine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE^® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and other NNRTIs should not be co-administered.
delavirdine	↑ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and delavirdine should not be co-administered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir (without ritonavir)	↓ atazanavir	Concomitant use of INTELENCE^® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE^® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir	↓ atazanavir ↑ etravirine	Concomitant use of INTELENCE^® with atazanavir/ritonavir may cause a significant decrease in atazanavir C_min and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE^® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE^® and darunavir/ritonavir (as part of the background regimen). INTELENCE^® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE^® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir (without ritonavir)	↑ amprenavir	Concomitant use of INTELENCE^® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE^® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir	↑ amprenavir	Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE^® and fosamprenavir/ritonavir have not been established. INTELENCE^® and fosamprenavir/ritonavir should not be co-administered.
indinavir (without ritonavir)	↓ indinavir	Concomitant use of INTELENCE^® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE^® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE^® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir (without ritonavir)	↑ nelfinavir	Concomitant use of INTELENCE^® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE^® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and ritonavir 600 mg b.i.d. should not be co-administered.
saquinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc	↔ etravirine ↓ maraviroc	When INTELENCE^® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE^® is needed.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir	↔ etravirine ↑ maraviroc	When INTELENCE^® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE^® is needed.
Other Agents
Antiarrhythmics: digoxin	↔ etravirine ↑ digoxin	For patients who are initiating a combination of INTELENCE^® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE^®, no dose adjustment of either INTELENCE^® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↓ antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE^®. INTELENCE^® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants: warfarin	↑ anticoagulants	Warfarin concentrations may be increased when co-administered with INTELENCE^®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE^®.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ etravirine	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE^® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antifungals: fluconazole, voriconazole	↑ etravirine ↔ fluconazole ↑ voriconazole	Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or fluconazole is needed.
		Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or voriconazole is needed.
Antifungals: itraconazole, ketoconazole, posaconazole	↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole	Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE^® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE^®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives: clarithromycin	↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin	Clarithromycin exposure was decreased by INTELENCE^®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials: rifampin, rifapentine	↓ etravirine	Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE^® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antimycobacterials: rifabutin	↓ etravirine ↓ rifabutin ↓ 25-O-desacetylrifabutin	If INTELENCE^® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended. If INTELENCE^® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam	↑ diazepam	Concomitant use of INTELENCE^® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids: dexamethasone (systemic)	↓ etravirine	Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE^®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ etravirine	Concomitant use of INTELENCE^® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and products containing St. John's wort should not be co-administered.
HMG-CoA Reductase Inhibitors: atorvastatin fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin	↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin	The combination of INTELENCE^® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE^® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE^® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE^® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↓ immunosuppressant	INTELENCE^® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics: methadone	↔ etravirine ↔ methadone	INTELENCE^® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil, vardenafil, tadalafil	↓ sildenafil ↓ N-desmethyl-sildenafil	INTELENCE^® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors: clopidogrel	↓ clopidogrel (active) metabolite	Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE^®. Alternatives to clopidogrel should be considered.

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Digoxin concentrations increased > 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril	58%	39%
Nitrendipine	57%	15%
Propafenone	35-85%	NA
Quinidine	100%	NA
Ranolazine	87%	88%
Ritonavir	NA	86%
Verapamil	50-75%	NA
Digoxin concentrations increased < 50%
Carvedilol	16%	14%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem	20%	NA
Nifedipine	45%	NA
Rabeprazole	29%	19%
Telmisartan	20%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anti-cancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclopramide, Miglitol, Neomycin, Rifampin, Salbutamol, St. John’s Wort, Sucralfate, Sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentrations changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

Table name:

Antiarrhythmics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Moricizine	Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinepherine	Can increase the risk of cardiac arrhythmias.
	Norepinephrine
	Dopamine
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers	Additive effects on AV node conduction can result in complete heart block.

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone(Ratio*)		Risperidone DoseRecommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6)Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twicedaily	1.4	1.5	Re-evaluate dosing. Donot exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Donot exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four timesdaily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference )		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 mg or 3 mg twice daily	1.4	1.5	Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	--	Reevaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	--
	40 mg/day -	4 mg/day	1.8	--
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 5 Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration with Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole(400 mg once daily)	+135%	+164%

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

Table name:

AED Co-administered	AED Concentration	TOPAMAX Concentration
NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.4, 4, 5.2, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with JUVISYNC
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin (100 mg/10 mg or 50 mg/10 mg JUVISYNC) daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC) daily
Grapefruit juice	Avoid grapefruit juice

Table name:

Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
HIV antiviral agents
Protease inhibitor: atazanavir	↓atazanavir ↑ tenofovir	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir ↑ tenofovir	Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir ↑ efavirenz	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir	Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine	Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when co-administered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor: raltegravir	↓ raltegravir	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: boceprevir	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: telaprevir	↓ telaprevir ↓ efavirenz	Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine ↓ efavirenz	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole ↓ hydroxy-itraconazole	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin ↑ 14-OH metabolite	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
rifampin	↓ efavirenz	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers: diltiazem	↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin ↓ pravastatin ↓ simvastatin	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comment
* see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.

Table name:

AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.

Table name:

Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
↑ Indicates increase. ↓ Indicates decrease.
Drug	Effect	Clinical Comment
ganciclovir	↑didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity.
methadone	↓didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxilfumarate	↑didanosine concentration	A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
↑ Indicates increase.
Drug or Drug Class	Effect	Clinical Comment
Drugs that may cause pancreatic toxicity	↑risk of pancreatitis	Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules is recommended [see Warnings and Precautions (5.1)].
Neurotoxic drugs	↑risk of neuropathy	Use with caution.[See Warnings and Precautions (5.6)].

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine ? valproate	Increased Lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name: Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA^®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours.Tadalafil: no more than 10 mg every 72 hours.Vardenafil: no more than 2.5 mg every 72 hours.Use with increased monitoring for adverse events.

Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Telaprevir^a	LEXIVA/ritonavir: ↓Amprenavir ↓Telaprevir	Coadministration of LEXIVA/ritonavir and telaprevir is not recommended.
HCV protease inhibitor: Boceprevir	LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted)	Coadministration of LEXIVA/ritonavir and boceprevir is not recommended. A pharmacokinetic interaction has been reported between boceprevir and some HIV protease inhibitors in combination with ritonavir, leading to decreased HIV protease inhibitor concentrations and, in some cases, decreased boceprevir concentrations.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine^a	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir^a	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir^a, nelfinavir^a	LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir^a	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir^a	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravir^a	LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV CCR5 co-receptor antagonist: Maraviroc^a	LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc	No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole^a, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine	↑Colchicine	Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutin^a	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan	↑Bosentan	Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatin^a	↑Atorvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol	↑Salmeterol	Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindrone^a	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. ^a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Proton pump inhibitors: Esomeprazole^a, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with VYTORIN
Verapamil, diltiazem	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	felodipinefinasteride	nizatidinenorfloxacin
amoxicillin	hydrocortisone	ofloxacin
ampicillin, with or without sulbactam	isoflurane isoniazid	omeprazole prednisone, prednisolone
atenolol	isradipine	ranitidine
azithromycin	influenza vaccine	rifabutin
caffeine, dietary ingestion	ketoconazo lelomefloxacin	roxithromycin sorbitol
cefaclor	mebendazole	(purgative doses do not
co-trimoxazole (trimethoprim and sulfamethoxazole)	medroxyprogesteronemethylprednisolone	inhibit theophylline absorption)
diltiazem	metronidazole	sucralfate
dirithromycin	metoprolol	terbutaline, systemic
enflurane	nadolol	terfenadine
famotidine	nifedipine	tetracycline
		tocainide

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Ritonavir or Concomitant Drug	Clinical Comment
		HIV-Antiviral Agents
HIV Protease Inhibitor: atazanavir	When co-administered with reduced doses of atazanavir and ritonavir ↑ atazanavir (↑ AUC, ↑ C_max, ↑ C_min)	Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. See the complete prescribing information for Reyataz^® (atazanavir) for details on co-administration of atazanavir 300 mg once daily with ritonavir 100 mg once daily.
HIV Protease Inhibitor: darunavir	When co-administered with reduced doses of ritonavir ↑ darunavir (↑ AUC, ↑ C_max, ↑ C_min)	See the complete prescribing information for Prezista^® (darunavir) for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily or darunavir 800 mg once daily with ritonavir 100 mg once daily.
HIV Protease Inhibitor: fosamprenavir	When co-administered with reduced doses of ritonavir ↑ amprenavir (↑ AUC, ↑ C_max, ↑ C_min)	See the complete prescribing information for Lexiva^® (fosamprenavir) for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily or fosamprenavir 1400 mg once daily with ritonavir 100 mg once daily.
HIV Protease Inhibitor: indinavir	When co-administered with reduced doses of indinavir and ritonavir ↑ indinavir (↔ AUC, ↓ C_max, ↑ C_min)	Alterations in concentrations are noted when reduced doses of indinavir are co-administered with NORVIR. Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV Protease Inhibitor: saquinavir	When co-administered with reduced doses of ritonavir ↑ saquinavir (↑ AUC, ↑ C_max, ↑ C_min)	See the complete prescribing information for Invirase^® (saquinavir) for details on co-administration of saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily. Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV Protease Inhibitor: tipranavir	When co-administered with reduced doses of ritonavir ↑ tipranavir (↑ AUC, ↑ C_max, ↑ C_min)	See the complete prescribing information for Aptivus^® (tipranavir) for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.
Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ ritonavir (↑AUC, ↑C_max, ↑ C_min)	Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry^® (maraviroc).
Integrase Inhibitor: Raltegravir	↓ raltegravir	The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic: tramadol, propoxyphene		A dose decrease may be needed for these drugs when co-administered with ritonavir.
Anesthetic: meperidine	↓ meperidine/ ↑ normeperidine (metabolite)	Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics: disulfiram/ metronidazole		Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics: disopyramide, lidocaine, mexiletine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents: dasatinib, nilotinib, vincristine, vinblastine	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin	↓ R-warfarin ↓↑ S-warfarin	Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is indicated.
Anticoagulant: rivaroxaban	↑ rivaroxaban	Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, clonazepam, ethosuximide	↑ anticonvulsants	Use with caution. A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants: divalproex, lamotrigine, phenytoin	↓ anticonvulsants	Use with caution. A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline	↑ antidepressants	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: desipramine	↑ desipramine	Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiemetic: dronabinol	↑ dronabinol	A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungal: ketoconazole itraconazole voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with ritonavir. Treatment of gout flares-co-administration of colchicine in patients on ritonavir: 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days. Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial: rifabutin	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial: rifampin	↓ ritonavir	May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations).
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic: quinine	↑ quinine	A dose decrease of quinine may be needed when co-administered with ritonavir.
β-Blockers: metoprolol, timolol	↑ Beta-Blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator: theophylline	↓ theophylline	Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers: diltiazem, nifedipine, verapamil	↑ calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin	↑ digoxin	Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on ritonavir: In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin)	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Inhaled or Intranasal Steroid e.g.: Fluticasone Budesonide	↑ glucocorticoids	Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone fentanyl	↓ methadone ↑ fentanyl	Dosage increase of methadone may be considered. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Neuroleptics: perphenazine, risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Oral Contraceptives or Patch Contraceptives: ethinyl estradiol	↓ ethinyl estradiol	Alternate methods of contraception should be considered.
PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^TM) with ritonavir: Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem	↑ sedative/hypnotics	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics: Parenteral midazolam	↑ midazolam	Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Steroids (systemic) e.g.: budesonide, dexamethasone, prednisone	↑ glucocorticoids	Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Stimulant: methamphetamine	↑ methamphetamine	Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin	melphalan	azapropazon	cimetidine
gentamicin		colchicine	ranitidine
tobramycin	Antifungals	diclofenac
vancomycin	amphotericin B	naproxen	Immunosuppressives
trimethoprim with sulfamethoxazole	ketoconazole	sulindac	tacrolimus

			Other Drugs
			fibric acid derivatives (e.g.,bezafibrate, fenofibrate)
			methotrexate

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/		colchicine
		dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		St. John's Wort
		terbinafine
		ticlopidine

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.

	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de pointes. Avoid concomitant use. (5.3)
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use. (5.3, 7.2)
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine. (7.1)
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug. (7.2)
Digoxin	Increased digoxin plasma concentration. (5.8, 7.1)

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Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name	Clinical Comment
Anticonvulsant agents: phenytoin, phenobarbital, carbamazepine	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors.
Antihistamines: astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: rifabutin,See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2. rifampin	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors or other coadministered antiviral agents.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John's wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors.
HMG-CoA reductase inhibitors: lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: alprazolam, midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

Table name:

Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of delavirdine or Concomitant Drug	Clinical Comment
↑ Indicates increase
↓ Indicates decrease
HIV-Antiviral Agents
Amprenavir	↑ Amprenavir	Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established.
DidanosineSee CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2.	↓ Delavirdine ↓ Didanosine	Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least one hour.
Indinavir	↑ Indinavir	A dose reduction of indinavir to 600 mg tid should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir	↑ Lopinavir ↑ Ritonavir	Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established.
Nelfinavir	↑ Nelfinavir ↓ Delavirdine	Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established. (See CLINICAL PHARMACOLOGY: Tables 1 and 2.)
Ritonavir	↑Ritonavir	Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established.
Saquinavir	↑ Saquinavir	A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered. (See CLINICAL PHARMACOLOGY: Table 1.) Appropriate doses with respect to safety, efficacy and pharmacokinetics, have not been established.
Other Agents
Acid blockers: antacids H₂Receptor antagonists: cimetidine, famotidine, nizatidine, ranitidine Proton pump inhibitors: omeprazole, lansoprazole	↓ Delavirdine	Doses of an antacid and RESCRIPTOR should be separated by at least one hour, because the absorption of delavirdine is reduced when coadministered with antacids.
	↓ Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines	↑ Amphetamines	Use with caution.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered.
Antiarrhythmics: bepridil	↑ Antiarrhythmics	Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone		Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: warfarin	↑ Warfarin	It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: clarithromycin	↑ Clarithromycin	When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.For patients with CL_CR<30 mL/min the dose of clarithromycin should be reduced by 75%.
Calcium channel blockers: amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil	↑ Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: dexamethasone	↓ Delavirdine	Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: sildenafil	↑ Sildenafil	Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period.
HMG-CoA reductase inhibitors: atorvastatin, cerivastatin, fluvastatin	↑ Atorvastatin ↑ Cerivastatin ↑ Fluvastatin	Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Narcotic analgesic: methadone	↑ Methadone	Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: ethinyl estradiol	↑ Ethinyl estradiol	Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.

Table name:

Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Concomitant Drug Class: Specific Drugs	Effect on Concentration of Atazanavir or Concomitant Drug	Clinical Comment
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules	↓ atazanavir ↓ didanosine	Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate	↓ atazanavir ↑ tenofovir	Tenofovir may decrease the AUC and C_min of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz	↓ atazanavir	Efavirenz decreases atazanavir exposure. In treatment-naive patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced patients: Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
nevirapine	↓ atazanavir ↑ nevirapine	Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure. Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors: saquinavir (soft gelatin capsules)	↑ saquinavir	Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
ritonavir	↑ atazanavir	If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR^® (ritonavir) for information on drug interactions with ritonavir.
others	↑ other protease inhibitor	REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
HCV Antiviral Agents
Protease Inhibitors: boceprevir	↓ atazanavir ↓ ritonavir	Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of REYATAZ/ritonavir and boceprevir is not recommended.
telaprevir	↓ telaprevir ↑ atazanavir	Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
Other Agents
Antacids and buffered medications	↓ atazanavir	Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ amiodarone, bepridil, lidocaine (systemic), quinidine	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin	↑ warfarin	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants	↑ tricyclic antidepressants	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone	↑ trazodone	Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiepileptics: carbamazepine	↓ atazanavir ↑ carbamazepine	Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with REYATAZ/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary.
phenytoin, phenobarbital	↓ atazanavir ↓ phenytoin ↓ phenobarbital	Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with REYATAZ without ritonavir. Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.
lamotrigine	↓ lamotrigine	Coadministration of lamotrigine and REYATAZ with ritonavir may decrease lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be required when coadministered with REYATAZ and ritonavir. Coadministration of lamotrigine and REYATAZ without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals: ketoconazole, itraconazole	REYATAZ/ritonavir: ↑ ketoconazole ↑ itraconazole	Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C_max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
voriconazole	REYATAZ/ritonavir in subjects with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ/ritonavir in subjects without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir	Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse events and loss of either voriconazole or atazanavir efficacy during the co-administration of voriconazole and REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.
Antigout: colchicine	↑ colchicine	REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment. Recommended dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterials: rifabutin	↑ rifabutin	A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolam^b	↑ midazolam	Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem	↑ diltiazem and desacetyl-diltiazem	Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
felodipine, nifedipine, nicardipine, and verapamil	↑ calcium channel blocker	Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan	↓ atazanavir ↑ bosentan	Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended. Coadministration of bosentan in patients on REYATAZ/ritonavir: For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.Coadministration of REYATAZ/ritonavir in patients on bosentan: Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H₂-Receptor antagonists	↓ atazanavir	Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
		In treatment-naive patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H₂-receptor antagonist. An H₂-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H₂-receptor antagonist. No single dose of the H₂-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
		In treatment-experienced patients: Whenever an H₂-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H₂-receptor antagonist. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H₂-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H₂-receptor antagonist, see Dosage and Administration (2.3) . REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H₂-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H₂-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone	↓ ethinyl estradiol ↑ norgestimate^c ↑ ethinyl estradiol ↑ norethindrone^d	Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone	REYATAZ ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
	REYATAZ/ritonavir ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin	↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir	Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine	↑ buprenorphine ↑ norbuprenorphine	Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Use of REVATIO^® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ]. The following dose adjustments are recommended for the use of ADCIRCA^® (tadalafil) with REYATAZ: Coadministration of ADCIRCA^® in patients on REYATAZ (with or without ritonavir): For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA^®: Avoid the use of ADCIRCA^® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA^® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
		Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA^® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS^® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ/ritonavir: Use LEVITRA^® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events. REYATAZ: Use LEVITRA^® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole	↓ atazanavir	Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
		In treatment-naive patients: The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
		In treatment-experienced patients: Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
HIV antiviral agents
Protease inhibitor: atazanavir	↓atazanavir ↑ tenofovir	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir ↑ tenofovir	Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir ↑ efavirenz	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir	Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine	Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor: raltegravir	↓ raltegravir	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: boceprevir	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: telaprevir	↓ telaprevir ↓ efavirenz	Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine ↓ efavirenz	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole ↓ hydroxy-itraconazole	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin ↑ 14-OH metabolite	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
rifampin	↓ efavirenz	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers: diltiazem	↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin ↓ pravastatin ↓ simvastatin	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Table 2 Steady-State Plasma Concentrations of Felbatol When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
AED Coadministered	AED Concentration	Felbatol® Concentration
Phenytoin	↑	↓
Valproate	↑	↔**
Carbamazepine (CBZ) *CBZ epoxide	↓ ↑	↓
Phenobarbital	↑	↓

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Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
Lopinavir plus ritonavir	Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with VYTORIN
Verapamil, diltiazem, dronedarone	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice	Avoid grapefruit juice

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name	Clinical Comment

Alpha 1-adrenoreceptor antagonist: alfuzosin	Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics: amiodarone, quinidine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial: rifampin	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products: St. John's wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
PDE5 inhibitor: sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension]	A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Proton Pump Inhibitors	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics: midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.

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Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine	↑ nelfinavir ↓ delavirdine
nevirapine	↓ nelfinavir (C_min)
Nucleoside Reverse Transcriptase Inhibitor: didanosine		It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Protease Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir	↑ nelfinavir ↑ indinavir
ritonavir	↑ nelfinavir
saquinavir	↑ saquinavir
Other Agents
Anti-coagulant: warfarin	warfarin	Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
Anti-convulsants:		May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine phenobarbital	↓ nelfinavir
Anti-convulsant:		Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin	↓ phenytoin
Anti-depressant: trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-gout colchicine	↑ colchicine	Treatment of gout flares– coadministration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares– coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT.
Anti-Mycobacterial:		It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)
Endothelin receptor antagonists: bosentan	↑ bosentan	Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor:		Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin	↑ atorvastatin
rosuvastatin	↑ rosuvastatin
Immuno-suppressants:		Plasma concentrations may be increased by VIRACEPT.
cyclosporine tacrolimus sirolimus	↑ immuno-suppressants	Plasma concentrations may be increased by VIRACEPT.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Macrolide Antibiotic: azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Narcotic Analgesic:		Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone	↓ methadone
Oral Contraceptive:		Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol	↓ ethinyl estradiol
PDE5 Inhibitors: sildenafil vardenafil tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated.
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
^* The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
This table is not all-inclusive.
HIV antiviral agents
Protease inhibitor: Fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: Atazanavir sulfate	↓ atazanavir^*	Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.
Protease inhibitor: Indinavir	↓ indinavir^*	The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and C_min were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
Protease inhibitor: Lopinavir/ritonavir	↓ lopinavir^*	Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA.
Protease inhibitor: Ritonavir	↑ ritonavir^* ↑ efavirenz^*	When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir.
Protease inhibitor: Saquinavir	↓ saquinavir^*	Should not be used as sole protease inhibitor in combination with SUSTIVA.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs.
CCR5 co-receptor antagonist: Maraviroc	↓ maraviroc^*	Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Integrase strand transfer inhibitor: Raltegravir	↓ raltegravir^*	SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: Boceprevir	↓ boceprevir^*	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: Telaprevir	↓ telaprevir^* ↓ efavirenz^*	Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant: Warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants: Carbamazepine	↓ carbamazepine^* ↓ efavirenz^*	There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
Phenytoin Phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: Bupropion	↓ bupropion^*	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
Sertraline	↓ sertraline^*	Increases in sertraline dosage should be guided by clinical response.
Antifungals: Voriconazole	↓ voriconazole^* ↑ efavirenz^*	SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See Dosage and Administration (2.1) and Clinical Pharmacology (12.3 , Tables 8 and 9) .]
Itraconazole	↓ itraconazole^* ↓ hydroxyitraconazole^*	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
Ketoconazole	↓ ketoconazole	Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.
Posaconazole	↓ posaconazole^*	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: Clarithromycin	↓ clarithromycin^* ↑ 14-OH metabolite^*	Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs , following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.
Antimycobacterials: Rifabutin	↓ rifabutin^*	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Rifampin	↓ efavirenz^*	If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.
Calcium channel blockers: Diltiazem	↓ diltiazem^* ↓ desacetyl diltiazem^* ↓ N-monodesmethyl diltiazem^*	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin	↓ atorvastatin^* ↓ pravastatin^* ↓ simvastatin^*	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate	↓ active metabolites of norgestimate^*	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant Etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immunosuppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Narcotic analgesic: Methadone	↓ methadone^*	Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Diluent	Storage
Diluent	Room Temp. (25°C)	Refrigerated (4°C)
Sterile Water	2 days	10 days
0.9% Sodium Chloride Solution	2 days	10 days
5% Dextrose Solution	2 days	10 days
10% Dextrose Solution	2 days	10 days
5% Dextrose + 0.9% Sodium Chloride Solution^*	2 days	Incompatible
5% Dextrose + 0.45% Sodium Chloride Solution	2 days	Incompatible
^* Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only.

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazaepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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blood dyscrasias —	diarrhea	hyperthyroidism
see CONTRAINDICATIONS	elevated temperature	poor nutritional state
cancer	hepatic disorders	steatorrhea
collagen vascular disease	infectious hepatitis	vitamin K deficiency
congestive heart failure	jaundice

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Classes of Drug
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations
5-lipoxygenase Inhibitor	Antiplatelet Drugs/Effects	Leukotriene Receptor Antagonist
Adrenergic Stimulants, Central	Antithyroid Drugs^†	Monoamine Oxidase Inhibitors
Alcohol Abuse Reduction	Beta-Adrenergic Blockers	Narcotics, prolonged
Preparations	Cholelitholytic Agents	Nonsteroidal Anti-
Analgesics	Diabetes Agents, Oral	Inflammatory Agents
Anesthetics, Inhalation	Diuretics^†	Proton Pump Inhibitors
Antiandrogen	Fungal Medications,	Psychostimulants
Antiarrhythmics^†	Intravaginal, Systemic^†	Pyrazolones
Antibiotics^†	Gastric Acidity and Peptic	Salicylates
Aminoglycosides (oral)	Ulcer Agents^†	Selective Serotonin
Cephalosporins, parenteral	Gastrointestinal	Reuptake Inhibitors
Macrolides	Prokinetic Agents	Steroids, Adrenocortical^†
Miscellaneous	Ulcerative Colitis Agents	Steroids, Anabolic (17-Alkyl
Penicillins, intravenous,	Gout Treatment Agents	Testosterone Derivatives)
high dose	Hemorrheologic Agents	Thrombolytics
Quinolones (fluoroquinolones)	Hepatotoxic Drugs	Thyroid Drugs
Sulfonamides, long acting	Hyperglycemic Agents	Tuberculosis Agents^†
Tetracyclines	Hypertensive Emergency Agents	Uricosuric Agents
Anticoagulants	Hypnotics^†	Vaccines
Anticonvulsants^†	Hypolipidemics^†	Vitamins^†
Antidepressants^†	Bile Acid-Binding Resins^†
Antimalarial Agents	Fibric Acid Derivatives
Antineoplastics^†	HMG-CoA Reductase Inhibitors^†
Antiparasitic/Antimicrobials
Specific Drugs Reported
acetaminophen	fenoprofen	paroxetine
alcoholIncreased and decreased PT/INR responses have been reported.	fluconazole	penicillin G, intravenous
allopurinol	fluorouracil	pentoxifylline
aminosalicylic acid	fluoxetine	phenylbutazone
amiodarone HCl	flutamide	phenytoin
argatroban	fluvastatin	piperacillin
aspirin	fluvoxamine	piroxicam
atenolol	gefitinib	pravastatin
atorvastatin	gemfibrozil	prednisone
azithromycin	glucagon	propafenone
bivalirudin	halothane	propoxyphene
capecitabine	heparin	propranolol
cefamandole	ibuprofen	propylthiouracil
cefazolin	ifosfamide	quinidine
cefoperazone	indomethacin	quinine
cefotetan	influenza virus vaccine	rabeprazole
cefoxitin	itraconazole	ranitidine
ceftriaxone	ketoprofen	rofecoxib
celecoxib	ketorolac	sertraline
cerivastatin	lansoprazole	simvastatin
chenodiol	lepirudin	stanozolol
chloramphenicol	levamisole	streptokinase
chloral hydrate	levofloxacin	sulfamethizole
chlorpropamide	levothyroxine	sulfamethoxazole
cholestyramine	liothyronine	sulfinpyrazone
cimetidine	lovastatin	sulfisoxazole
ciprofloxacin	mefenamic acid	sulindac
cisapride	methimazole	tamoxifen
clarithromycin	methyldopa	tetracycline
clofibrate	methylphenidate	thyroid
warfarin sodium overdose	methylsalicylate ointment (topical)	ticarcillin
cyclophosphamide	metronidazole	ticlopidine
danazol	miconazole	tissue plasminogen
dextran	(intravaginal, oral, systemic)	activator (t-PA)
dextrothyroxine	moricizine hydrochloride	tolbutamide
diazoxide	nalidixic acid	tramadol
diclofenac	naproxen	trimethoprim/sulfamethoxazole
dicumarol	neomycin	urokinase
diflunisal	norfloxacin	valdecoxib
disulfiram	ofloxacin	valproate
doxycycline	olsalazine	vitamin E
erythromycin	omeprazole	zafirlukast
esomeprazole	oxandrolone	zileuton
ethacrynic acid	oxaprozin
ezetimibe	oxymetholone
fenofibrate	pantoprazole

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edema	hypothyroidism
hereditary coumarin resistance	nephrotic syndrome
hyperlipemia

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Classes of Drugs
also: diet high in vitamin K unreliable PT/INR determinations
Adrenal Cortical Steroid Inhibitors	Antipsychotic Medications	Hypolipidemics^†
Antacids	Antithyroid Drugs^†	Bile Acid-Binding Resins^†
Antianxiety Agents Antiarrhythmics^†	Barbiturates Diuretics^†	HMG-CoA Reductase Inhibitors^†
Anticonvulsants^†	Enteral Nutritional Supplements	Immunosuppressives
Antidepressants^†	Fungal Medications, Systemic^†	Oral Contraceptives,
Antihistamines	Gastric Acidity and Peptic Ulcer Agents^†	Estrogen Containing
Antineoplastics^†	Hypnotics^†	Selective Estrogen Receptor Modulators
		Steroids, Adrenocortical^†
		Tuberculosis Agents^† Vitamins^†
Specific Drugs Reported:
alcoholIncreased and decreased PT/INR responses have been reported.	warfarin sodium underdosage	phenytoin
aminoglutethimide	cyclophosphamide	pravastatin
amobarbital	dicloxacillin	prednisone
atorvastatin	ethchlorvynol	primidone
azathioprine	glutethimide	propylthiouracil
butabarbital	griseofulvin	raloxifene
butalbital	haloperidol	ranitidine
carbamazepine	meprobamate	rifampin
chloral hydrate	6-mercaptopurine	secobarbital
chlordiazepoxide	methimazole	spironolactone
chlorthalidone	moricizine hydrochloride	sucralfate
cholestyramine	nafcillin	trazodone
clozapine	paraldehyde	vitamin C (high dose)
corticotropin	pentobarbital	vitamin K
cortisone	phenobarbital

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin, with or without sulbactam	methylprednisolone
atenolol	metronidazole
azithromycin	metoprolol
caffeine, dietary ingestion	nadolol
cefaclor	nifedipine
co-trimoxazole (trimethoprim and	nizatidine
sulfamethoxazole)	norfloxacin
diltiazem	ofloxacin
dirithromycin	omeprazole
enflurane prednisone,	prednisolone
famotidine	ranitidine
felodipine	rifabutin
finasteride	roxithromycin
hydrocortisone	sorbitol (purgative doses do not inhibit
isoflurane	theophylline absorption)
isoniazid	sucralfate
isradipine	terbutaline, systemic
influenza vaccine	terfenadine
ketoconazole	tetracycline
lomefloxacin	tocainide

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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AED Co-administration	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table II. Clinically significant drug interactions with theophylline.*
Drug	Type of Interaction	Effect†
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may berequired to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg ofwhiskey) decreases theophylline clearance for up to24 hours	30% increase
Allopurinol	Decreases theophylline clearance at allopurinoldoses 600 mg/day	25% increase
Aminoglutethimide	Increases theophylline clearance by induction ofmicrosomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibitingcytochrome P450 1A2	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentratrionsof adenosine, a potent CNS depressant, whiletheophylline blocks adenosine receptors.	Larger diazepam doses may be requiredto produce desired level of sedation.Discontinuation of theophylline withoutreduction of diazepam dose may resultin respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibitinghydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea,nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophyllineclearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by asimilar amount.
Estrogen	Estrogen containing oral contraceptives decreasetheophylline clearance in a dose-dependentfashion. The effect of progesterone on theophyllineclearance in unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium tocatecholamines, theophylline increases release ofendogenous catecholamines.	Increased risk of ventriculararrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizurethreshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achievea therapeutic serum concentrationincreased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX,higher dose MTX may have a greatereffect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% increase
Pancuronium	Theophylline may antagonize non-depolarizingneuromuscular blocking effects;possibly due tophosphodiesterase inhibition.	Larger dose of pancuronium may berequired to achieve neuromuscularblockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks ofconcurrent PB.
Phenytoin	Phenytoin increases theophylline clearance byincreasing microsomal enzyme activity.	Serum theophylline and phenytoinconcentrations decrease about 40%.
Propafenone	Decreases theophylline clearance andpharmacologic interaction.	40% increase. Beta-2 blocking effectmay decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologicinteraction.	100% increase Beta-2 blocking effectmay decrease efficacy of theophylline
Rifampin	Increases theophylline clearance by increasingcytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasingdemethylation and hydroxylation. Decreases renalclearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renalclearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending ontroleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary digestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

Table name:

Antibiotics
ciprofloxacin
gentamicin
tobramycin
trimethoprim with sulfamethoxazole
vancomycin

Antineoplastic
melphalan

Antifungals
amphotericin B
ketoconazole

Anti-Inflammatory Drugs
azapropazon
colchicine
diclofenac
naproxen
sulindac

Gastrointestinal Agents
cimetidine
ranitidine

Immunosuppressives
tacrolimus

Other Drugs
fibric acid derivatives
(e.g., bezafibrate, fenofibrate)

Table name:

Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/dalfopristin		colchicine
				danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

Table name:

Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan	terbinafine
rifampin	oxcarbazepine	octreotide	ticlopidine
	phenobarbital	orlistat	St. John's Wort
	phenytoin	sulfinpyrazone

Table name:

Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with VYTORIN
Verapamil, diltiazem	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

Table name:

Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum and Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum and Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Rifabutin Interaction StudiesND - No data
AUC - Area under the Concentration vs. Time Curve
Cmax - Maximum serum concentration
Coadministered Drugs	Effect on Rifabutin	Effect on Coadministered Drug	Comments
ANTIVIRALS
Amprenavir	2.9-fold ↑ AUC, 2.2-fold ↑ Cmax	No significant change in kinetics.	A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted.
Delavirdine	ND	Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM)	Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h.
Didanosine	No significant change in kinetics.	No significant change in kinetics at steady state.
Fosamprenavir/ritonavir	64% ↑ AUC - Drug plus active metabolite	35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir)	Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir
Indinavir	204% ↑ in AUC	32%↓ in AUC
Lopinavir/ritonavir	5.7-fold ↑ AUC, 3.4 fold ↑ Cmax	No significant change in lopinavir kinetics.	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary.
Saquinavir	ND	40% ↓ in AUC
Ritonavir	4 fold increase in AUC, 2.5 fold increase in Cmax	ND	In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered.
Tipranavir/ritonavir[133]	2.9-fold ↑ AUC, 1.7-fold ↑ Cmax	No significant change in tipranavir kinetics.	Therapeutic drug monitoring of rifabutin is recommended.
Zidovudine	No significant change in kinetics.	Approximately 32%↓ in Cmax and AUC	A large controlled clinical study has shown that these changes are of no clinical relevance.
ANTIFUNGALS
ANTIFUNGALS	82% ↑ in AUC	No significant change in steady-state plasma concentrations
Itraconazole	ND	70% to 75% ↓ in Cmax and AUC	One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole.
Posaconazole	31%↑ Cmax, 72%↑ AUC	43%↓ Cmax, 49%↓ AUC	If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration.
Voriconazole	195%↑ Cmax, 331%↑ AUC - voriconazole dosed at 400 mg twice daily	Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily.	If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone	ND	Approximately 27% to 40% ↓ in AUC	Study conducted in HIV infected patients (rapid and slow acetylators).
Sulfamethoxazole-Trimethoprim	No significant change in Cmax and AUC	Approximately 15% to 20% ↓ in AUC	In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant.
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin	No PK interaction	No PK interaction
Clarithromycin	Approximately 77% ↑ in AUC	Approximately 50%↓ in AUC	Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin
ANTI-TB (Tuberculosis)
Ethambutol	ND	No significant change in AUC or Cmax
Isoniazid	ND	Pharmacokinetics not affected
Pyrazinamide	ND	ND	Study data being evaluated.
OTHER
Methadone	ND	No significant effect	No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated.
Ethinylestradiol	ND	35%↓ AUC 20%↓ Cmax	Patients should be advised to use other methods of contraception.
Norethindrone	ND	46%↓ AUC	Patients should be advised to use other methods of contraception.
Tacrolimus	ND	ND	Authors report that rifabutin decreases tacrolimus trough blood levels.
Theophylline	ND	No significant change in AUC or Cmax compared with baseline.

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Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase carbamazepine epoxide levels.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table IV. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	lomefloxacin mebendazole
amoxicillin	medroxyprogesterone
ampicillin, with or without sulbactam	methylprednisolone metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine nizatidine
cefaclor	norfloxacin
co-trimoxazole (trimethoprim and sulfamethoxazole)	ofloxacin omeprazole prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol (purgative doses do not inhibit theophylline absorption)
felodipine
finasteride
hydrocortisone
insoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Quinidine	NA	54-83%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Ritonavir	NA	86%
Digoxin concentrations increased less than 50%
Amiodarone	17%	40%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Propafenone	28%	29%
Quinine	NA	34-38%
Spironolactone	NA	44%
Verapamil	NA	24%
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs that were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 3
SUPRANE (desflurane, USP) MAC with Fentanyl or Midazolam Mean ± SD (percent reduction)
Dose	18-30 years	31-65 years
No fentanyl	6.4 ± 0.0	6.3 ± 0.4
3 µg/kg fentanyl	3.5 ± 1.9 (46%)	3.1 ± 0.6 (51%)
6 µg/kg fentanyl	3.0 ± 1.2 (53%)	2.3 ± 1.0 (64%)
No midazolam	6.9 ± 0.1	5.9 ± 0.6
25 µg/kg midazolam	-	4.9 ± 0.9 (16%)
50 µg/kg midazolam	-	4.9 ± 0.5 (17%)

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Table 4
Dosage of Muscle Relaxant Causing 95% Depression in Neuromuscular Blockade
Desflurane Concentration	Mean ED₉₅ (µg/kg)
Desflurane Concentration	Pancuronium	Atracurium	Succinylcholine	Vecuronium
0.65 MAC 60% N₂O/O₂	26	123	-	-
1.25 MAC 60% N₂O/O₂	18	91	-	-
1.25 MAC O₂	22	120	362	19

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_max SS (Peak plasma concentration)	AUC_SS(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents.	Carefully monitor blood glucose (5.11, 7.3)

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
NC = Less than 10% change in plasma concentration. NE = Not Evaluated.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Table 10: Pharmacokinetic Interaction Data for Fosaprepitant/Aprepitant and Coadministered Midazolam
Dose of fosaprepitant/ aprepitant	Dose of Midazolam	Observed Drug Interactions
fosaprepitant 150 mg on Day 1	oral 2 mg on Days 1 and 4	AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4
fosaprepitant 100 mg on Day 1	oral 2 mg	oral midazolam AUC ↑ 1.6-fold
oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5	oral 2 mg SD on Days 1 and 5	oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5
oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3	intravenous 2 mg prior to 3-day regimen of aprepitant and on Days 4, 8 and 15	intravenous midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8 and AUC ↓ 4% on Day 15
oral aprepitant 125 mg	intravenous 2 mg given 1 hour after aprepitant	intravenous midazolam AUC ↑ 1.5-fold

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decease]
Valproic acid	400 to 2800	600 to 1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	Lopinavir/ritonavir 400/100 mg tablets can be used twice daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those >45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/ritonavir	The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_{max SS} (Peak plasma concentration)	AUC_SS(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Table 3: Summary of AED interactions with Topiramate
AED Co-administered	AED Concentration	Topiramate Concentration
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM – Topiramate
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC 40%	decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA ( 7.4 ) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , ) 2.6 5.1 7.1 7.2 7.3 7.4
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
^a Should be administered at least 4 hours prior to WELCHOL
^b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
^c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
^d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug	cyclosporine^c, glimepiride^a, glipizide^a, glyburide^a, levothyroxine^a, olmesartan medoxomil^a, and oral contraceptives containing ethinyl estradiol and norethindrone^a
Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug	metformin extended release (ER)^d
Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL	phenytoin^a, warfarin^b
Drugs that do not interact with colesevelam based on in vitro or in vivo testing	aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoin^a, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarin^b

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Table 3: Summary of AED interactions with Topiramate
AED Co-administered	AED Concentration	Topiramate Concentration
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM – Topiramate
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC 40%	decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the oral solution formulation is taken within 2 hours of these products (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 5: Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX EC
Drug	Effect	Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
^a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
ganciclovir	↑ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with VIDEX EC with caution. Monitor for didanosine-associated toxicity.
methadone	↓ didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after VIDEX EC.
tenofovir disoproxil fumarate	↑ didanosine concentration	A dose reduction of VIDEX EC to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.^a 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 6: Predicted Drug Interactions with VIDEX EC
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase.
^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended [see Warnings and Precautions (5.1) ].
^b [See Warnings and Precautions (5.6) .]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution.^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution.^b

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Table IIl Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	hydrocortisone	nizatidine
amoxicillin	isoflurane	norfloxacin
ampicillin, with or without sulbactam	isoniazid	ofloxacin
atenolol	isradipine	omeprazole
azithromycin	influenza vaccine	prednisone, prednisolone
caffeine, dietary ingestion	ketoconazole	ranitidine
cefaclor	lomefloxacin	rifabutin
co-trimoxazole	mebendazole	roxithromycin
(trimethoprim and sulfamethoxazole) diltiazem	medroxyprogesterone	sorbitol
dirithromycin	methylprednisolone	(purgative doses do not inhibit theophylline absorption)
enflurane	metronidazole	sucralfate
famotidine	metoprolol	terbutaline, systemic
felodipine	nadolol	terfenadine
finasteride	nifedipine	tetracycline tocainide

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 7 Summary of AED Interactions with Trileptal
AED Coadministered	Dose of AED (mg/day)	Trileptal Dose (mg/day)	Influence of Trileptal on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Table 7: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 10 and 11]
Concomitant Drug Class: Drug Name	Effect on Concentration of Darunavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine	↔ darunavir ↔ didanosine	Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)	↑ darunavir ↑ indinavir	The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir	↓ darunavir ↔ lopinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir	↓ darunavir ↔ saquinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-Antiviral Agents: CCR5 co-receptor antagonists
Maraviroc	↑ maraviroc	Maraviroc concentrations are increased when co-administered with PREZISTA/rtv. When used in combination with PREZISTA/rtv, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics: bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone	↑ antiarrhythmics	Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin	↑ digoxin	The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant: warfarin	↓ warfarin ↔ darunavir	Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant: carbamazepine	↔ darunavir ↑ carbamazepine	The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant: phenobarbital, phenytoin	↔ darunavir ↓ phenytoin ↓ phenobarbital	Co-administration of PREZISTA/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant: trazodone, desipramine	↑ trazodone ↑ desipramine	Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.
Anti-infective: clarithromycin	↔ darunavir ↑ clarithromycin	No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals: ketoconazole, itraconazole, voriconazole	↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied)	Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
		Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
		Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimycobacterial: rifabutin	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin	Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel Blockers: felodipine, nifedipine, nicardipine	↑ calcium channel blockers	Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Systemic: dexamethasone	↓ darunavir	Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin	↑ pravastatin ↑ atorvastatin ↑ rosuvastatin	Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/ritonavir.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence: methadone, buprenorphine, buprenorphine/naloxone	↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite)	No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics: risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone	↓ ethinyl estradiol ↓ norethindrone	Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors: sildenafil, vardenafil, tadalafil	↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir)	Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine	↔ darunavir ↓ sertraline ↓ paroxetine	If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.2, 4, 5.2, 7.1, 7.2, 7.3, 7.4, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol, verapamil, diltiazem	Contraindicated with SIMCOR
Amiodarone, amlodipine, ranolazine	Do not exceed 1000/20 mg SIMCOR daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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DRUGS	EFFECT
Aspirin w/anti-inflammatory agents	Increased ulcerogenic effects.
Butalbital w/coumarin anticoagulants	Decreased effect of anticoagulant because of increased metabolism resulting from enzyme induction.
Butalbital w/tricyclic antidepressants	Decreased blood levels of the antidepressant.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on concentration of Nevirapine or Concomitant drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol andNorethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events.
Fosamprenavir	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine.A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir /Ritonavir	The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease
				[CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase	25% decrease
			[CI: 2% increase, 24% increase]	[CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800	nc ^, Pediatrics	30% decrease
		>1200-2400	up to 40% increaseMean increase in adults at high Oxcarbazepine doses	[CI: 3% decrease, 48% decrease]
			[CI: 12% increase, 60% increase]
Valproic acid	400-2800	600-1800	nc	18% decrease
				[CI: 13% decrease, 40% decrease]

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine gluronidation). ?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50% Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 7: Summary of AED Interactions with Oxcarbazepine

AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [Cl: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [Cl: 2% increase, 24% increase]	25% decrease [Cl: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [Cl: 12% increase, 60% increase]	30% decrease [Cl: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [Cl: 13% decrease, 40% decrease]
¹nc denotes a mean change of less than 10% ²Pediatrics ³Mean increase in adults at high oxcarbazepine doses

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 4 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate)	↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake)	The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. ^, This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily. ↓ ketoconazole ^,	Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
H₂-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ rilpivirine ^, (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine ^, (famotidine taken 2 hours before rilpivirine)	The combination of COMPLERA and H₂-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H₂-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin	↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics: methadone	↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone (when used with tenofovir)	No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkanizing Agents	Decreased plasma salicylate levels.

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparintreated patients.
Pyrazinamide	Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased T₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone, ketone bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant	Increased bleeding

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Drug	Description
Corticosteroids	Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

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Drug	Description
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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AED Coadministered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 1. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Azithromycin
NA - Not Available ^* - 90% Confidence interval not reported Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when coadministered with azithromycin and 71 ng/mL when coadministered with placebo.
Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Mean C_max	Mean AUC
Atorvastatin	10 mg/day x 8 days	500 mg/day PO on days 6 to 8	12	0.83 (0.63 to 1.08)	1.01 (0.81 to 1.25)
Carbamazepine	200 mg/day x 2 days, then 200 mg BID x 18 days	500 mg/day PO for days 16 to 18	7	0.97 (0.88 to 1.06)	0.96 (0.88 to 1.06)
Cetirizine	20 mg/day x 11 days	500 mg PO on day 7, then 250 mg/day on days 8 to 11	14	1.03 (0.93 to 1.14)	1.02 (0.92 to 1.13)
Didanosine	200 mg PO BID x 21 days	1,200 mg/day PO on days 8 to 21	6	1.44 (0.85 to 2.43)	1.14 (0.83 to 1.57)
Efavirenz	400 mg/day x 7 days	600 mg PO on day 7	14	1.04^*	0.95^*
Fluconazole	200 mg PO single dose	1,200 mg PO single dose	18	1.04 (0.98 to 1.11)	1.01 (0.97 to 1.05)
Indinavir	800 mg TID x 5 days	1,200 mg PO on day 5	18	0.96 (0.86 to 1.08)	0.90 (0.81 to 1.00)
Midazolam	15 mg PO on day 3	500 mg/day PO x 3 days	12	1.27 (0.89 to 1.81)	1.26 (1.01 to 1.56)
Nelfinavir	750 mg TID x 11 days	1,200 mg PO on day 9	14	0.90 (0.81 to 1.01)	0.85 (0.78 to 0.93)
Rifabutin	300 mg/day x 10 days	500 mg PO on day 1, then 250 mg/day on days 2 to 10	6	See footnote below	NA
Sildenafil	100 mg on days 1 and 4	500 mg/day PO x 3 days	12	1.16 (0.86 to 1.57)	0.92 (0.75 to 1.12)
Theophylline	4 mg/kg IV on days 1, 11, 25	500 mg PO on day 7, 250 mg/day on days 8 to 11	10	1.19 (1.02 to 1.40)	1.02 (0.86 to 1.22)
Theophylline	300 mg PO BID x 15 days	500 mg PO on day 6, then 250 mg/day on days 7 to 10	8	1.09 (0.92 to 1.29)	1.08 (0.89 to 1.31)
Triazolam	0.125 mg on day 2	500 mg PO on day 1, then 250 mg/day on day 2	12	1.06^*	1.02^*
Trimethoprim/ Sulfamethoxazole	160 mg/800 mg/day PO x 7 days	1,200 mg PO on day 7	12	0.85 (0.75 to 0.97)/0.90 (0.78 to 1.03)	0.87 (0.80 to 0.95)/0.96 (0.88 to 1.03)
Zidovudine	500 mg/day PO x 21 days	600 mg/day PO x 14 days	5	1.12 (0.42 to 3.02)	0.94 (0.52 to 1.70)
Zidovudine	500 mg/day PO x 21 days	1,200 mg/day PO x 14 days	4	1.31 (0.43 to 3.97)	1.30 (0.69 to 2.43)

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Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs (see PRECAUTIONS, Drug Interactions).
NA – Not available ^* - 90% Confidence interval not reported Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.
Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Mean C_max	Mean AUC
Efavirenz	400 mg/day x 7 days	600 mg PO on day 7	14	1.22 (1.04 to 1.42)	0.92^*
Fluconazole	200 mg PO single dose	1,200 mg PO single dose	18	0.82 (0.66 to 1.02)	1.07 (0.94 to 1.22)
Nelfinavir	750 mg TID x 11 days	1,200 mg PO on day 9	14	2.36 (1.77 to 3.15)	2.12 (1.80 to 2.50)
Rifabutin	300 mg/day x 10 days	500 mg PO on day 1, then 250 mg/day on days 2 to 10	6	See footnote below	NA

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists GlucocorticoidsOctreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-Containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) SulfonamidesTolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate OrlistatSucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport — but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil MitotaneTamoxifen	Androgens / Anabolic Steroids Asparaginase GlucocorticoidsSlow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - PhenylbutazoneSalicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins PhenobarbitalRifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day)Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives- Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline)- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones- Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem- Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators- (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use)Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUCss_(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Reevaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg 4 times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Drugs That May Potentiate Renal Dysfunction
Antibiotics	Antineoplastics	Anti-Inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin	melphalan	azapropazon	cimetidine
gentamicin		colchicine	ranitidine
tobramycin	Antifungals	diclofenac
vancomycin	amphotericin B	naproxen	Immunosuppressives
trimethoprim	ketoconazole	sulindac	tacrolimus
with
sulfamethoxazole			Other Drugs
			fibric acid derivatives
			(e.g., bezafibrate,
			fenofibrate)

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Table 1. Selected Drugs that Are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by Itraconazole¹
Drug plasma concentration increased by itraconazole
Antiarrhythmics	digoxin, dofetilide², quinidine², disopyramide
Anticonvulsants	carbamazepine
Antimycobacterials	rifabutin
Antineoplastics	busulfan, docetaxel, vinca alkaloids
Antipsychotics	pimozide²
Benzodiazepines	alprazolam, diazepam, midazolam,^{2, 3} triazolam²
Calcium Channel Blockers	dihydropyridines (including felodipine² and nisoldipine²), verapamil
Gastrointestinal Motility Agents	cisapride²
HMG CoA-Reductase Inhibitors	atorvastatin, cerivastatin, lovastatin², simvastatin²
Immunosuppressants	cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics	oral hypoglycemics
Protease Inhibitors	indinavir, ritonavir, saquinavir
Other	methadone², levacetylmethadol (levomethadyl)², ergot alkaloids², halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl

Decrease plasma concentration of itraconazole
Anticonvulsants	carbamazepine, phenobarbital, phenytoin
Antimycobacterials	isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers	antacids, H₂-receptor antagonists, proton pump inhibitors
Non-nucleoside Reverse Transcriptase Inhibitors	nevirapine

Increase plasma concentration of itraconazole
Macrolide Antibiotics	clarithromycin, erythromycin
Protease Inhibitors	indinavir, ritonavir

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenz* nevirapine	↓ etravirine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE^® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and other NNRTIs should not be co-administered.
delavirdine	↑ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and delavirdine should not be co-administered.
rilpivirine	↓ rilpivirine ↔ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir (without ritonavir)	↓ atazanavir	Concomitant use of INTELENCE^® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE^® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir	↓ atazanavir ↑ etravirine	Concomitant use of INTELENCE^® with atazanavir/ritonavir may cause a significant decrease in atazanavir C_min and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE^® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE^® and darunavir/ritonavir (as part of the background regimen). INTELENCE^® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE^® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir (without ritonavir)	↑ amprenavir	Concomitant use of INTELENCE^® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE^® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir	↑ amprenavir	Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE^® and fosamprenavir/ritonavir have not been established. INTELENCE^® and fosamprenavir/ritonavir should not be co-administered.
indinavir (without ritonavir)	↓ indinavir	Concomitant use of INTELENCE^® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE^® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE^® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir (without ritonavir)	↑ nelfinavir	Concomitant use of INTELENCE^® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE^® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc	↔ etravirine ↓ maraviroc	When INTELENCE^® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE^® is needed.
maraviroc/darunavir/ritonavir †	↔ etravirine ↑ maraviroc	When INTELENCE^® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE^® is needed.
Other Agents
Antiarrhythmics: digoxin	↔ etravirine ↑ digoxin	For patients who are initiating a combination of INTELENCE^® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE^®, no dose adjustment of either INTELENCE^® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↓ antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE^®. INTELENCE^® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants: warfarin	↑ anticoagulants	Warfarin concentrations may be increased when co-administered with INTELENCE^®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE^®.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ etravirine	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE^® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antifungals: fluconazole, voriconazole	↑ etravirine ↔ fluconazole ↑ voriconazole	Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or fluconazole is needed.
		Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or voriconazole is needed.
Antifungals: itraconazole, ketoconazole, posaconazole	↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole	Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE^® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE^®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives: clarithromycin	↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin	Clarithromycin exposure was decreased by INTELENCE^®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimalarials: artemether/lumefantrine	↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine	Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE^®.
Antimycobacterials: rifampin, rifapentine	↓ etravirine	Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE^® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antimycobacterials: rifabutin	↓ etravirine ↓ rifabutin ↓ 25-O-desacetylrifabutin	If INTELENCE^® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE^® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam	↑ diazepam	Concomitant use of INTELENCE^® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids: dexamethasone (systemic)	↓ etravirine	Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE^®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ etravirine	Concomitant use of INTELENCE^® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and products containing St. John's wort should not be co-administered.
Hepatitis C Virus (HCV) Direct-Acting Antivirals: telaprevir	↔ etravirine ↓ telaprevir	There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE^®.
HMG-CoA Reductase Inhibitors: atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin	↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin	The combination of INTELENCE^® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE^® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE^® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE^® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↓ immunosuppressant	INTELENCE^® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence: buprenorphine, buprenorphine/naloxone, methadone	↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone	INTELENCE^® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE^® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil, tadalafil, vardenafil	↓ sildenafil ↓ N-desmethyl-sildenafil	INTELENCE^® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors: clopidogrel	↓ clopidogrel (active) metabolite	Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE^®. Alternatives to clopidogrel should be considered.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Drug		Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).		Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic anti-depressants.		Pressor response increased.
Phenylephrine with ergot alkaloids.		Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.		Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.		Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.		Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.		Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.		Synergistic adrenergic response.

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Table 3: Summary of AED Interactions with Topiramate
AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase

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Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
Antiretroviral agents
Protease inhibitor: atazanavir	↓atazanavir concentration ↑ tenofovir concentration	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir concentration	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir concentration	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir concentration ↑ tenofovir concentration	A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir concentration ↑ efavirenz concentration	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir concentration	Should not be used as sole protease inhibitor in combination with ATRIPLA.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc concentration	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine concentration	Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin concentration	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine concentration ↓ efavirenz concentration	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant concentration ↓ efavirenz concentration	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion concentration	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline concentration	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole concentration ↓ hydroxy-itraconazole concentration	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole concentration	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole concentration	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin concentration ↑ 14-OH metabolite concentration	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial: rifampin	↓ efavirenz concentration	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers: diltiazem	↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone concentration	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.^*
albuterol, systemic and inhaled	diltiazem	medroxyprogesterone	roxithromycin
albuterol, systemic and inhaled	dirithromycin	methylprednisolone	Sorbitol (purgative doses do not inhibit theophylline absorption)
amoxicillin	enflurane	metronidazole
ampicillin, with or without sulbactam	famotidine	metoprolol
	felodipine	nadolol
	finasteride	nifedipine
atenolol	hydrocortisone	nizatidine	sucralfate
azithromycin	isoflurane	norfloxacin	terbutaline, systemic
caffeine, dietary ingestion	isoniazid	ofloxacin	terfenadine
caffeine, dietary ingestion	isradipine	omeprazole	tetracycline
cefaclor	influenza vaccine	prednisone, prednisolone	tocainide
co-trimoxazole (trimethoprim and sulfamethoxazole)	ketoconazole	prednisone, prednisolone
	lomefloxacin	ranitidine
	mebendazole	rifabutin
^* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* Delavirdine Etravirine Rilpivirine	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin* Rifabutin* Rifampin*	↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* Ketoconazole* Itraconazole	↑Nevirapine ↓ Ketoconazole ↓ Itraconazole	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception
* The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Antibiotics	Antineoplastic	Antifungals	Anti-Inflammatory Drugs	Gastrointestinal Agents	Immunosuppressives	Other Drugs
ciprofloxacin	melphalan	amphotericin B	azapropazon	cimetidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate)
gentamicin		ketoconazole	colchicine	ranitidine		methotrexate
tobramycin			diclofenac
trimethoprim with sulfamethoxazole			naproxen
vancomycin			sulindac

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/ dalfopristin		colchicine
				danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Antibiotics	Anticonvulsants	Other Drugs / Dietary Supplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between VIRAMUNE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* Delavirdine Etravirine Rilpivirine	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin* Rifabutin* Rifampin*	↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* Ketoconazole* Itraconazole	↑Nevirapine ↓ Ketoconazole ↓ Itraconazole	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient𕢙s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine ↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓ Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* Delavirdine Etravirine Rilpivirine	↓Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin* Rifabutin* Rifampin*	↓Clarithromycin ↑14-OH clarithromycin ↑Rifabutin ↓ Nevirapine	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* Ketoconazole* Itraconazole	↑Nevirapine ↓ Ketoconazole ↓ Itraconazole	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40% May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration		Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen		Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Drug or Drug Class
Dopamine / Dopamine Agonists		Glucocorticoids		Octreotide
Effect - Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥1 μg/kg/min); Glucocorticoids (hydrocortisone≥100 mg/day or equivalent); Octreotide ( >100 μg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Drug or Drug Class
Aminoglutethimide Amiodarone		Iodide (including iodine-containing Radiographic contrast agents) Lithium		Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide
Effect - Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Drug or Drug Class
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Effect - Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Drug or Drug Class
Antacids - Aluminum & Magnesium Hydroxides - Simethicone		Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate		Cation Exchange Resins - Kayexalate Ferrous Sulfate Sucralfate
Effect - Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives		Estrogens (oral) Heroin / Methadone 5-Fluorouracil		Mitotane Tamoxifen
Drugs that may decrease serum TBG concentration
Androgens / Anabolic Steroids			Glucocorticoids
Asparaginase			Slow Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Drug or Drug Class
Furosemide ( > 80 mg IV) Heparin Hydantoins			Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
Effect - Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Drug or Drug Class
Carbamazepine	Hydantoins		Phenobarbital		Rifampin
Effect - Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Drug or Drug Class
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day)			Glucocorticoids - (e.g., Dexamethasone ≥4 mg/day) Propylthiouracil (PTU)
Effect - Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Drug or Drug Class
Anticoagulants (oral)
- Coumarin Derivatives			- Indandione Derivatives
Effect - Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Drug or Drug Class
Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline)			- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Effect - Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Drug or Drug Class
Antidiabetic Agents - Biguanides		- Meglitinides - Thiazolidinediones		- Sulfonylureas - Insulin
Effect - Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Drug or Drug Class
Cardiac Glycosides
Effect - Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Drug or Drug Class
Cytokines		- Interferon-α		- Interleukin-2
Effect - Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Drug or Drug Class
Growth Hormones		- Somatrem		- Somatropin
Effect - Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Drug or Drug Class
Ketamine
Effect - Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Drug or Drug Class
Methylxanthine Bronchodilators - (e.g., Theophylline)
Effect - Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Drug or Drug Class
Radiographic Agents
Effect - Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Drug or Drug Class
Sympathomimetics
Effect - Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Drug or Drug Class
Chloral Hydrate Diazepam Ethionamide Lovastatin		Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium		Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
Effect - These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

Table name:

Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy, has not been established.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated.	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 4: Summary of AED Interactions with Topiramate
AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase
NC = Less than 10% change in plasma concentration AED = Antiepileptic drug NE = Not Evaluated TPM = Topiramate

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Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release
Drug	Effect	Clinical Comment
ganciclovir	↑ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release with caution. Monitor for didanosine-associated toxicity.
methadone	↓ didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of dianosine is didanosine delayed-release. Patients should be closely monitored for adequate clinical response when didanosine delayed-release is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction one hour after didanosine	Administer nelfinavir one hour after didanosine delayed-release.
tenofovir disoproxil fumarate	↑ didanosine concentration	A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. • 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) • 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min Patients should be monitored for didanosine-associated toxicities and clinical response.
↑ indicates increase ↓ indicates decrease

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Table 6: Predicted Drug Interactions with Didanosine Delayed-Release
Drug or Drug Class	Effect	Clinical Comment
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release is recommended [see Warnings and Precautions (5.1) ].
Neurotoxic drugs	↑ risk of neuropathy	Use with caution. [See Warnings and Precautions (5.6)]
↑ Indicates increase

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓ Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500/125 mg twicedaily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/ritonavir	The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.7, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, fibrates	Avoid VYTORIN
Cyclosporine, danazol	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, verapamil	Do not exceed 10/20 mg VYTORIN daily
Diltiazem	Do not exceed 10/40 mg VYTORIN daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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AED Coadministered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high Oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI:13% decrease, 40% decrease]

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolismreported with smoking of marijuana; effect similar to that following smoking tobacco

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comment
* see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)] . Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)] .
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)] .
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)] . KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)] .
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR greater then 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (less then 200 mg/day) or itraconazole (less then 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction] .
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)] . If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)] . The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 11:Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 14 and 15]
Concomitant Drug Class: Drug Name	Effect on Concentration of Darunavir or Concomitant Drug	Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine	↔ darunavir ↔ didanosine	Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)	↑ darunavir ↑ indinavir	The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir	↓ darunavir ↔ lopinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir	↓ darunavir ↔ saquinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc	↑ maraviroc	Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics: bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone	↑ antiarrhythmics	Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin	↑ digoxin	The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant: warfarin	↓ warfarin ↔ darunavir	Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant: carbamazepine	↔ darunavir ↑ carbamazepine	The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant: phenobarbital, phenytoin	↔ darunavir ↓ phenytoin ↓ phenobarbital	Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant: trazodone, desipramine	↑ trazodone ↑ desipramine	Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective: clarithromycin	↔ darunavir ↑ clarithromycin	No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals: ketoconazole, itraconazole, voriconazole	↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied)	Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
		Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
		Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimalarials: artemether/lumefantrine	↓ artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir	The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation.
Antimycobacterial: rifabutin	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin	Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel Blockers: felodipine, nifedipine, nicardipine	↑ calcium channel blockers	Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Systemic: dexamethasone	↓ darunavir	Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents: NS3-4A protease inhibitors: boceprevir telaprevir	↓ darunavir ↓ boceprevir ↓ telaprevir	Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin	↑ pravastatin ↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence: methadone, buprenorphine, buprenorphine/naloxone	↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite)	No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics: risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone	↓ ethinyl estradiol ↓ norethindrone	Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors: sildenafil, vardenafil, tadalafil	↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir)	Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine	↔ darunavir ↓ sertraline ↓ paroxetine	If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.

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Coadministered Drug	Dosing Schedule		Effect on ActiveMoiety (Risperidone + 9- Hydroxy-Risperidone(Ratio*)		Risperidone DoseRecommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6)Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twicedaily	1.4	1.5	Re-evaluate dosing. Donot exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Donot exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards.Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four timesdaily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE^® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. nevirapine	↓ etravirine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE^® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and other NNRTIs should not be co-administered.
delavirdine	↑ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and delavirdine should not be co-administered.
rilpivirine	↓ rilpivirine ↔ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir (without ritonavir)	↓ atazanavir	Concomitant use of INTELENCE^® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE^® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir	↓ atazanavir ↑ etravirine	Concomitant use of INTELENCE^® with atazanavir/ritonavir may cause a significant decrease in atazanavir C_min and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE^® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE^® and darunavir/ritonavir (as part of the background regimen). INTELENCE^® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE^® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir (without ritonavir)	↑ amprenavir	Concomitant use of INTELENCE^® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE^® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir	↑ amprenavir	Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE^® and fosamprenavir/ritonavir have not been established. INTELENCE^® and fosamprenavir/ritonavir should not be co-administered.
indinavir (without ritonavir)	↓ indinavir	Concomitant use of INTELENCE^® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE^® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE^® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir (without ritonavir)	↑ nelfinavir	Concomitant use of INTELENCE^® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE^® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc	↔ etravirine ↓ maraviroc	When INTELENCE^® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE^® is needed.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir	↔ etravirine ↑ maraviroc	When INTELENCE^® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE^® is needed.
Other Agents
Antiarrhythmics: digoxin	↔ etravirine ↑ digoxin	For patients who are initiating a combination of INTELENCE^® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE^®, no dose adjustment of either INTELENCE^® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↓ antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE^®. INTELENCE^® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants: warfarin	↑ anticoagulants	Warfarin concentrations may be increased when co-administered with INTELENCE^®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE^®.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ etravirine	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE^® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antifungals: fluconazole, voriconazole	↑ etravirine ↔ fluconazole ↑ voriconazole	Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or fluconazole is needed.
		Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or voriconazole is needed.
Antifungals: itraconazole, ketoconazole, posaconazole	↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole	Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE^® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE^®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives: clarithromycin	↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin	Clarithromycin exposure was decreased by INTELENCE^®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimalarials: artemether/lumefantrine	↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine	Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE^®.
Antimycobacterials: rifampin, rifapentine	↓ etravirine	Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE^® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antimycobacterials: rifabutin	↓ etravirine ↓ rifabutin ↓ 25-O-desacetylrifabutin	If INTELENCE^® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE^® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam	↑ diazepam	Concomitant use of INTELENCE^® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids: dexamethasone (systemic)	↓ etravirine	Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE^®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ etravirine	Concomitant use of INTELENCE^® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and products containing St. John's wort should not be co-administered.
Hepatitis C Virus (HCV) Direct-Acting Antivirals: telaprevir	↔ etravirine ↓ telaprevir	There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE^®.
HMG-CoA Reductase Inhibitors: atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin	↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin	The combination of INTELENCE^® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE^® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE^® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE^® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↓ immunosuppressant	INTELENCE^® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence: buprenorphine, buprenorphine/naloxone, methadone	↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone	INTELENCE^® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE^® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil, tadalafil, vardenafil	↓ sildenafil ↓ N-desmethyl-sildenafil	INTELENCE^® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors: clopidogrel	↓ clopidogrel (active) metabolite	Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE^®. Alternatives to clopidogrel should be considered.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaled	lomefloxacin
amoxicillin	mebendazole
ampicillin, with or without sulbactam	medroxyprogesterone
atenolol	methylprednisolone
azithromycin	metronidazole
caffeine, dietary ingestion	metoprolol
cefaclor	nadolol
co-trimoxazole (trimethoprim and sulfamethoxazole)	nifedipine
diltiazem	nizatidine
dirithromycin	norfloxacin
enflurane	ofloxacin
famotidine	omeprazole
felodipine	prednisone, prednisolone
finasteride	ranitidine
hydrocortisone	rifabutin
isoflurane	roxithromycin
isoniazid	sorbitol (purgative doses do not inhibit theophylline absorption)
isradipine	sucralfate
influenza vaccine	terbutaline, systemic
ketoconazole	terfenadine
	tetracycline
	tocainide
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Strong CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, fluoxetine) inhibitors will increase ABILIFY drug concentrations; reduce ABILIFY dose by one-half when used concomitantly (2.6, 7.1), except when used as adjunctive treatment with antidepressants (2.6) CYP3A4 inducers (eg, carbamazepine) will decrease ABILIFY drug concentrations; double ABILIFY dose when used concomitantly (2.6, 7.1)

See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decease]
Valproic acid	400 to 2800	600 to 1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.

AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

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Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
Lopinavir plus ritonavir	Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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AED Coadministered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Antibiotics	Antineoplastic	Antifungals	Anti- Inflammatory Drugs	Gastrointestinal Agents	Immunosuppressives	Other Drugs
ciprofloxacingentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin	melphalan	amphotericin Bketoconazole	azapropazoncolchicine diclofenacnaproxen sulindac	cimetidine ranitidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate)

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
		quinupristin/		colchicine
	voriconazole	dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Antibiotics	Anticonvulsants	Other Drugs/DietarySupplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

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Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin ^•150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Phenylephrine:
Drug	Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).	Cardiac pressor response potentiated. May cause acute hypertensive crisis.

Phenylephrine with tricyclic antidepressants.	Pressor response increased.

Phenylephrine with ergot alkaloids.	Excessive rise in blood pressure.

Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.	Tachycardia or other arrhythmias may occur.

Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.	Cardiostimulating effects blocked.

Phenylephrine with atropine sulfate.	Reflex bradycardia blocked; pressor response enhanced.

Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.	Pressor response decreased.

Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.	Synergistic adrenergic response.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

Table name:

DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkanizing Agents	Decreased plasma salicylate levels.

Table name:

DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

Table name:

LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased T3 uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone, ketone bodies	False positive FeCl3 in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

Table name:

Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE^® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. nevirapine	↓ etravirine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE^® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and other NNRTIs should not be co-administered.
delavirdine	↑ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and delavirdine should not be co-administered.
rilpivirine	↓ rilpivirine ↔ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir (without ritonavir)	↓ atazanavir	Concomitant use of INTELENCE^® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE^® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir	↓ atazanavir ↑ etravirine	Concomitant use of INTELENCE^® with atazanavir/ritonavir may cause a significant decrease in atazanavir C_min and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE^® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE^® and darunavir/ritonavir (as part of the background regimen). INTELENCE^® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE^® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir (without ritonavir)	↑ amprenavir	Concomitant use of INTELENCE^® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE^® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir	↑ amprenavir	Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE^® and fosamprenavir/ritonavir have not been established. INTELENCE^® and fosamprenavir/ritonavir should not be co-administered.
indinavir (without ritonavir)	↓ indinavir	Concomitant use of INTELENCE^® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE^® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE^® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir (without ritonavir)	↑ nelfinavir	Concomitant use of INTELENCE^® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE^® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc	↔ etravirine ↓ maraviroc	When INTELENCE^® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE^® is needed.
maraviroc/darunavir/ritonavir	↔ etravirine ↑ maraviroc	When INTELENCE^® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE^® is needed.
Other Agents
Antiarrhythmics: digoxin	↔ etravirine ↑ digoxin	For patients who are initiating a combination of INTELENCE^® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE^®, no dose adjustment of either INTELENCE^® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↓ antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE^®. INTELENCE^® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants: warfarin	↑ anticoagulants	Warfarin concentrations may be increased when co-administered with INTELENCE^®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE^®.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ etravirine	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE^® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antifungals: fluconazole, voriconazole	↑ etravirine ↔ fluconazole ↑ voriconazole	Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or fluconazole is needed.
		Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or voriconazole is needed.
Antifungals: itraconazole, ketoconazole, posaconazole	↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole	Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE^® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE^®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives: clarithromycin	↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin	Clarithromycin exposure was decreased by INTELENCE^®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials: rifampin, rifapentine	↓ etravirine	Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE^® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antimycobacterials: rifabutin	↓ etravirine ↓ rifabutin ↓ 25-O-desacetylrifabutin	If INTELENCE^® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE^® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam	↑ diazepam	Concomitant use of INTELENCE^® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids: dexamethasone (systemic)	↓ etravirine	Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE^®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ etravirine	Concomitant use of INTELENCE^® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and products containing St. John's wort should not be co-administered.
HMG-CoA Reductase Inhibitors: atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin	↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin	The combination of INTELENCE^® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE^® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE^® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE^® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↓ immunosuppressant	INTELENCE^® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence: buprenorphine, buprenorphine/naloxone, methadone	↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone	INTELENCE^® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE^® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil, tadalafil, vardenafil	↓ sildenafil ↓ N-desmethyl-sildenafil	INTELENCE^® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors: clopidogrel	↓ clopidogrel (active) metabolite	Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE^®. Alternatives to clopidogrel should be considered.

Table name:

Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone) (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors			AUC	C_max
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name: In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Coadministration of STRIBILD in patients on tadalafil: Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events.

Table 5 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration↑ = Increase, ↓ = Decrease, ⇔ = No Effect	Clinical Comment
Acid Reducing Agents: AntacidsIndicates that a drug-drug interaction trial was conducted. (for example aluminum and magnesium hydroxide)	↓ elvitegravir	Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours.
Proton Pump Inhibitors H₂ Receptor Antagonists	⇔ elvitegravir	No dose adjustment is needed when STRIBILD is combined with either H₂ receptor antagonists or proton pump inhibitors.
Antiarrhythmics: e.g. amiodarone bepridil digoxin disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine	↑ antiarrhythmics ↑ digoxin	Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.
Antibacterials: clarithromycin telithromycin	↑ clarithromycin ↑ telithromycin ↑ cobicistat	Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD. Patients with CLcr greater than or equal to 60 mL/min: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/min and 60 mL/min: The dose of clarithromycin should be reduced by 50%. Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD.
Anticoagulants: warfarin	Effect on warfarin unknown	Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD.
Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin	↑ carbamazepine ↓ elvitegravir ↓ cobicistat	Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered.
clonazepam ethosuximide	↑ clonazepam ↑ ethosuximide	Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. paroxetine Tricyclic Antidepressants (TCAs) e.g. amitriptyline desipramine imipramine nortriptyline buproprion trazodone	↑ SSRIs ↑ TCAs ↑ trazodone	Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response is recommended.
Antifungals: itraconazole ketoconazole voriconazole	↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑voriconazole	Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
Anti-gout: colchicine	↑ colchicine	STRIBILD should not be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin rifapentine	↓ elvitegravir ↓ cobicistat	Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.
Beta-Blockers: e.g. metoprolol timolol	↑ beta-blockers	Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.
Calcium Channel Blockers: e.g. amlodipine diltiazem felodipine nicardipine nifedipine verapamil	↑ calcium channel blockers	Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD.
Corticosteroid: Systemic: dexamethasone	↓ elvitegravir ↓ cobicistat	Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Coadministration of bosentan in patients on STRIBILD: In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of STRIBILD in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin	↑ atorvastatin	Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.
Hormonal Contraceptives: norgestimate/ethinyl estradiol	↑ norgestimate ↓ ethinyl estradiol	The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non hormonal) methods of contraception can be considered.
Immuno-suppressants: e.g. cyclosporine sirolimus tacrolimus	↑ immuno-suppressants	Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.
Inhaled Beta Agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Neuroleptics: e.g. perphenazine risperidone thioridazine	↑ neuroleptics	A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.
Phosphodiesterase-5 (PDE5) Inhibitors: sildenafil tadalafil vardenafil	↑ PDE5 inhibitors	Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH). The following dose adjustments are recommended for the use of tadalafil with STRIBILD: Coadministration of tadalafil in patients on STRIBILD:
Sedative/hypnotics: Benzodiazepines: e.g. Parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem	↑ sedatives/hypnotics	Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.^*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	felodipine	norfloxacin
systemic and inhaled	finasteride	ofloxacin
amoxicillin	hydrocortisone	omeprazole
ampicillin,	isoflurane	prednisone, prednisolone
with or without sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide
famotidine	nizatidine

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport — but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole

	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ

Low-dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkalizing Agents	Decreased plasma salicylate levels.

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
NC = Less than 10% change in plasma concentration. NE = Not Evaluated.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.^*
albuterol, systemic and inhaled	diltiazem	medroxyprogesterone	roxithromycin
albuterol, systemic and inhaled	dirithromycin	methylprednisolone	Sorbitol (purgative doses do not inhibit theophylline absorption)
amoxicillin	enflurane	metronidazole
ampicillin, with or without sulbactam	famotidine	metoprolol
	felodipine	nadolol
	finasteride	nifedipine
atenolol	hydrocortisone	nizatidine	sucralfate
azithromycin	isoflurane	norfloxacin	terbutaline, systemic
caffeine, dietary ingestion	isoniazid	ofloxacin	terfenadine
caffeine, dietary ingestion	isradipine	omeprazole	tetracycline
cefaclor	influenza vaccine	prednisone, prednisolone	tocainide
co-trimoxazole (trimethoprim and sulfamethoxazole)	ketoconazole	prednisone, prednisolone
	lomefloxacin	ranitidine
	mebendazole	rifabutin
^* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high Oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI:13% decrease, 40% decrease]

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant	Increased bleeding

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Drug	Description
Corticosteroids	Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

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Drug	Description
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 3: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values^a
Drug	Didanosine Dosage	n	AUC of Didanosine (90% CI)	Cmax of Didanosine (90% CI)
tenofovir,^b 300 mg once daily with a light meal^c	400 mg single dose fasting 2 h before tenofovir	26	↑ 48% (31, 67%)	↑ 48% (25, 76%)
tenofovir,^b 300 mg once daily with a light meal^c	400 mg single dose with tenofovir and a light meal	25	↑ 60% (44, 79%)	↑ 64% (41, 89%)
tenofovir,^b 300 mg once daily with a light meal^c	200 mg single dose with tenofovir and a light meal 250 mg single dose with tenogovir and a light meal 325 mg single dose with tenofovir and a light meal	33 33 33	↑ 16% (6, 27%)^d ↔(-13, 5%)^e ↑ 13% (3, 24%)	↓ 12% (-25, 3%)^d ↓ 20% (-32, -7%)^e ↓ 11% (-24, 4%)^e
↑ indicates increase. ↓ indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. ^a All studies conducted in healthy volunteers ≥60kg with creatinine clearance ≥60 mL/min. ^b tenofovir disporoxil fumarate. ^c 373 kcalories, 8.2 grams fat. ^d Compared with didanosine delayed-release capsules 250 mg administered alone under fasting coniditions. ^e Compared with didanosine delayed-release capsules 400 mg administered alone under fasting conditions.

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Table 4: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values^a
↔ Indicates no change, or mean increase or decrease of less than 10%.
* The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed. † All studies conducted in healthy volunteers ≥ 60 kg with creatinine clearance ≥ 60 mL/min. ‡ Tenofovir disoproxil fumarate. § 373 kcalories, 8.2 grams fat.
Drug	Didanosine Dosage	n	AUC of Coadministered Drug	Cmax of Coadministered Drug
ciprofloxacin, 750 mg single dose indinavir, 800 mg single dose ketoconazole, 200 mg single dose tenofovir,‡ 300 mg once daily with a light meal§ tenofovir,‡ 300 mg once daily with a light meal§	400 mg single dose 400 mg single dose 400 mg single dose 400 mg single dose fasting 2h before tenofovir 400 mg single dose with tenofovir anda light meal	16 23 21 25 25	↔ ↔ ↔ ↔ ↔	↔ ↔ ↔ ↔ ↔

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Table 5: Results of Drug Interaction Studies with Buggered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine plasma AUC and Cmax Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS, Drug Interactions )
Drug	Didanosine Dosage	n	AUC Didanosine (95% CI)	Cmax of Didanosine (95% CI)
allopurinol, Renally impaired, 300 mg/day	200 mg single dose	2	↑312%	↑232%
healthy volunteer, 300 mg/day for 7 days	400 mg single dose	14	↑113%	↑69%
ganciclovir, 1000 mg q8h, 2 h after didanosine	200 mg q12h	12	↑111%	NA
methadone, chronic maintenance dose	200 mg single dose	16, 10^a	↓57%	↓66%
tenofovir,^b 300 mg once daily 1 h after didanosine	250^c or 400 mg once daily for 7 days	14	↑44% (31, 59%)^d	↔28% (11, 48%)^d
No Clinically Significant Interactions Observed
ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine	200 mg q12h for 3 days	8^e	↓16%	↓28%
ininavir, 800 mg single dose simultaneous	200 mg single dose	16	↔	↔
1 h before didanosine	200 mg single dose	16	↓17% (-27, -7%)^d	↓13% (-28, 5%)^d
ketoconazole, 200 mg/day for 4 days, 2 h before didanosine	375 mg q12h for 4 days	12^e	↔	↓12%
loperamide, 4 mg q6h for 1 day	300 mg single dose	12^e	↔	↓23%
metoclopramide, 10 mg single dose	300 mg single dose	12^e	↔	↑13%
ranitidine, 150 mg 2 h before didansine	375 mg single dose	12^e	↑14%	↑13%
rifabutin, 300 or 600 mg/day for 12 days	167 or 250 mg q12h for 12 days	11	↑13% (-1, 27%)	↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days	200 mg q12h for 4 days	12	↓13% (0, 23%)	↓16% (5, 26%)
stavudine, 40 mg q12h for 4 days	100 mg q12h for 4 days	10	↔	↔
sulfamethoxazole, 1000 mg single dose	200 mg single dose	8^e	↔	↔
trimethoprim, 200 mg single dose	200 mg single dose	8^e	↔	↑17% (-23, 77%)
zidovudine, 200 mg q7h for 3 days	200 mg q12h for 3 days	8^e	↔	↔
↑ indicates increase ↓ indicates decrease ↔ indicates no change, or mean increase or decrease of <10%. ^a Parellel-group design; entries are subjects receiving combination and control regimens, respectively. ^b tenogovir disoproxil fumarate ^c patients <60 kg with creatinine clearance >60 mL/min. ^d 90% CI ^e HIV-infected patients N/A Not available

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Table 6: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
No Clinically Significant Interaction Observed
Drug	Didanosine Dosage	n	AUC of Coadministered Drug (95% CI)	Cmax of Coadministered Drug (95% CI)
dapsone, 100 mg single dose	200 mg q12h for 14 days	6^a	↔	↔
delaviridine, 400 mg single dose simultaneous	125 or 200 mg q12h	12^a	↓32%^b	↓53%^b
1 hr before didanosine	125 or 200 mg q12h	12^a	↑20%	↑18%
ganciclovir, 1000 mg q8h, 2h after didanosine	200 mg q12h	12^a	↓21%	NA
nelfinavir, 750 mg single dose, 1 h after didanosine	200 mg single dose	10^a	↑12%	↔
ranitidine, 150 mg single dose, 2 h before didanosine	375 mg single dose	12^a	↓16%	↔
ritonavir, 600 mg q12h for 4 days	200 mg q12h for 4 days	12	↔	↔
stavudine, 40 mg q12h for 4 days	100 mg q12h for 4 days	10^a	↔	↑17%
sulfamethoxazole, 1000 mg single dose	200 mg single dose	8^a	↓11% (-17, -4%)	↓12% (-28, 8%)
tenofovir,^C 300 mg once daily 1 h after didanosine	250^d or 400 mg once daily for 7 days	14	↔	↔
trimethoprim, 200 mg single dose	200 mg single dose	8^a	↑10% (-9, 34%)	↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3 days	200 mg q12h for 3 days	6^a	↓10% (-27, 11%)	↓16.5% (-53, 47%)
↑ indicates increase. ↓indicates decrease. ↔ indicates no change, or mean increase or decrease of <10%. ^aHIV-infected patients. ^bThis result is probably related to the bugger and is not expected to occur with didanosine delayed-release capsules. ^ctenofovir disoproxil fumarate. ^dpatients <60 kg with creatinine clearance >60 mL/min.NA Not available

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to for information regarding table. PRECAUTIONS, Drug Interactions
albuterol, systemic and inhaled	felodipinefinasteride	nizatidinenorfloxacin
amoxicillin	hydrocortisone	ofloxacin
ampicillin, with or without sulbactam	isoflurane isoniazid	omeprazole prednisone, prednisolone
atenolol	isradipine	ranitidine
azithromycin	influenza vaccine	rifabutin
caffeine, dietary ingestion	ketoconazo lelomefloxacin	roxithromycin sorbitol
cefaclor	mebendazole	(purgative doses do not
co-trimoxazole (trimethoprim and sulfamethoxazole)	medroxyprogesteronemethylprednisolone	inhibit theophylline absorption)
diltiazem	metronidazole	sucralfate
dirithromycin	metoprolol	terbutaline, systemic
enflurane	nadolol	terfenadine
famotidine	nifedipine	tetracycline
		tocainide

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%

Ketoconazole (400 mg once daily)	+135%	+164%

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50% Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Table 4: Summary of AED Interactions with Topiramate
^a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM = Topiramate
AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasea	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideb	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

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Table 3
SUPRANE (desflurane, USP) MAC with Fentanyl or Midazolam Mean ± SD (percent reduction)
Dose	18-30 years	31-65 years
No fentanyl	6.4 ± 0.0	6.3 ± 0.4
3 µg/kg fentanyl	3.5 ± 1.9 (46%)	3.1 ± 0.6 (51%)
6 µg/kg fentanyl	3.0 ± 1.2 (53%)	2.3 ± 1.0 (64%)
No midazolam	6.9 ± 0.1	5.9 ± 0.6
25 µg/kg midazolam	-	4.9 ± 0.9 (16%)
50 µg/kg midazolam	-	4.9 ± 0.5 (17%)

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Table 4
Dosage of Muscle Relaxant Causing 95% Depression in Neuromuscular Blockade
Desflurane Concentration	Mean ED₉₅ (µg/kg)
Desflurane Concentration	Pancuronium	Atracurium	Succinylcholine	Vecuronium
0.65 MAC 60% N₂O/O₂	26	123	-	-
1.25 MAC 60% N₂O/O₂	18	91	-	-
1.25 MAC O₂	22	120	362	19

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AED Coadministered	AED Concentration	Topiramate Concentration
a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increasea	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideb	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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blood dyscrasias -
see CONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure

diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice

hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

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edema
hereditary coumarin resistance
hyperlipemia

hypothyroidism
nephrotic syndrome

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 11:Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 14 and 15]
Concomitant Drug Class: Drug Name	Effect on Concentration of Darunavir or Concomitant Drug	Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine	↔ darunavir ↔ didanosine	Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)	↑ darunavir ↑ indinavir	The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir	↓ darunavir ↔ lopinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir	↓ darunavir ↔ saquinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc	↑ maraviroc	Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics: bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone	↑ antiarrhythmics	Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin	↑ digoxin	The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant: warfarin	↓ warfarin ↔ darunavir	Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant: carbamazepine	↔ darunavir ↑ carbamazepine	The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant: phenobarbital, phenytoin	↔ darunavir ↓ phenytoin ↓ phenobarbital	Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant: trazodone, desipramine	↑ trazodone ↑ desipramine	Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective: clarithromycin	↔ darunavir ↑ clarithromycin	No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals: ketoconazole, itraconazole, voriconazole	↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied)	Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
		Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
		Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimalarials: artemether/lumefantrine	↓ artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir	The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation.
Antimycobacterial: rifabutin	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin	Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel Blockers: felodipine, nifedipine, nicardipine	↑ calcium channel blockers	Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Systemic: dexamethasone	↓ darunavir	Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents: NS3-4A protease inhibitors: boceprevir telaprevir	↓ darunavir ↓ boceprevir ↓ telaprevir	Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin	↑ pravastatin ↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence: methadone, buprenorphine, buprenorphine/naloxone	↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite)	No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics: risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone	↓ ethinyl estradiol ↓ norethindrone	Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors: sildenafil, vardenafil, tadalafil	↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir)	Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine	↔ darunavir ↓ sertraline ↓ paroxetine	If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant	Increased bleeding

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Drug	Description
Corticosteroids	Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

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Drug	Description
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine	↓ Efavirenz	Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be decreased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be increased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

Table name:

Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants: warfarin, rivaroxaban	↑ rivaroxaban	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants: lamotrigine, valproate	↓ lamotrigine ↓ or ↔ valproate	Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments [see Clinical Pharmacology (12.3)].
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone	↓ lopinavir ↑ glucocorticoids	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV-Protease Inhibitor: boceprevir	↓ lopinavir ↓ boceprevir ↓ ritonavir	It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see Clinical Pharmacology (12.3)].
HCV-Protease Inhibitor: telaprevir	↓ telaprevir ↔ lopinavir	It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected [see Clinical Pharmacology (12.3)].
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide	↑ glucocorticoids	Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics: methadone,* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
↑ Indicates increase. ↓ Indicates decrease.
Drug	Effect	Clinical Comment
ganciclovir	↑didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity.
methadone	↓didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxilfumarate	↑didanosine concentration	A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.

Table name:

Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
↑ Indicates increase.
Drug or Drug Class	Effect	Clinical Comment
Drugs that may cause pancreatic toxicity	↑risk of pancreatitis	Use only with extreme caution.
Neurotoxic drugs	↑risk of neuropathy	Use with caution.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

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Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

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Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) (Tables 12 and 13) for magnitude of interaction]
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV Antiviral Agents: Reverse Transcriptase Inhibitors
Delavirdine	↑ nelfinavir (C_min) ↓ delavirdine	Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established.
Nevirapine	↓ nelfinavir (C_min)	Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established.
Didanosine	↔ nelfinavir	There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
HIV Antiviral Agents: Protease Inhibitors
Indinavir	↑ nelfinavir ↑ indinavir	Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
Ritonavir	↑ nelfinavir ↔ ritonavir	Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established.
Saquinavir	↑ nelfinavir ↑ saquinavir	Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
ANTICOAGULANT
Warfarin	Warfarin	Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
ANTICONVULSANTS
Carbamazepine Phenobarbital Phenytoin	↓ nelfinavir ↓ phenytoin	Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
ANTIDEPRESSANT
Trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIGOUT
Colchicine	↑ colchicines	Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity. Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
Rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)	It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
ENDOTHELIN RECEPTOR ANTAGONIST
Bosentan	↑ bosentan	Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin Rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day.
IMMUNOSUPPRESSANTS
Cyclosporine Tacrolimus Sirolimus	↑ immuno-suppressants ↑ nelfinavir	Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir.
INHALED BETA AGONIST
Salmeterol	↑ salmeterol	Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INHALED/NASAL STEROID
Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
MACROLIDE ANTIBIOTIC
Azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
NARCOTIC ANALGESIC
Methadone	↓ methadone	Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT.
HORMONAL CONTRACEPTIVES
Ethinyl estradiol Norethindrone	↓ ethinyl estradiol ↓ norethindrone	Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered.
PDE5 INHIBITORS
Sildenafil Vardenafil Tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.
PROTON PUMP INHIBITORS
Omeprazole	↓ nelfinavir	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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1A2	2C9	3A4	2C19
Warfarin	Warfarin	Alprazolam	Omeprazole
Theophylline
Propranolol
Tizanidine

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants	Increased Bleeding

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Drug	Description of Interaction
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

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Drug	Description of Interaction
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Laboratory Tests	Effects of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with highdose salicylate therapy (2-5 g qd)
5 Hydroxyindole AceticAcid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ inGerhardt reaction; red color persists with boiling
17-OH Corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP34A inhibitors (e.g. itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Antibiotics	Anti-neoplastics	Antifungals	Anti-inflammatory Drugs	Gastrointestinal Agents	Immuno-suppressives	Other Drugs
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole	melphalan	amphotericin B ketoconazole	azapropazon colchicine diclofenac naproxen sulindac	cimetidine ranitidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem nicardipine verapamil	fluconazole itraconazole ketoconazole voriconazole	azithromycin clarithromycin erythromycin quinupristin/ dalfopristin	methylprednisolone	allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodone oral contraceptives

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Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin rifampin	carbamazepine oxcarbazepine phenobarbital phenytoin	bosentan octreotide orlistat sulfinpyrazone terbinafine ticlopidine	St. John’s Wort

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Table 9: Summary of Effect of Coadministered Drugs on Exposure to LATUDA in Healthy Subjects or Patients with Schizophrenia
Coadministered drug	Dose schedule		Effect on LATUDA pharmacokinetics		Recommendation
	Coadministered drug	LATUDA	C _max	AUC
Ketoconazole (strong CYP3A4 inhibitor)	400 mg/day for 5 days	10 mg single dose	6.9-times LATUDA alone	9-times LATUDA alone	Should not be coadministered with LATUDA
Diltiazem (moderate CYP3A4 inhibitor)	240 mg/ day for 5 days	20 mg single dose	2.1- times LATUDA alone	2.2- times LATUDA alone	LATUDA dose should not exceed 40 mg/day if coadministered
Rifampin (strong CYP3A4 inducer)	600 mg/day for 8 days	40 mg single dose	1/7^th of LATUDA alone	1/5^th of LATUDA alone	Should not be coadministered with LATUDA
Lithium	600 mg BID for 8 days	120 mg/day for 8 days	0.9-times LATUDA alone	1.1- times LATUDA alone	No LATUDA dose adjustment required.

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AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drugs That May Potentiate Renal Dysfunction
Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole	melphalan	azapropazon colchicine diclofenac naproxen sulindac	cimetidine ranitidine
	Antifungals		cimetidine ranitidine
	amphotericin B ketoconazole		Immunosuppressives
			tacrolimus
			Other Drugs
			fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

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Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem nicardipine verapamil	fluconazole itraconazole ketoconazole voriconazole	azithromycin clarithromycin erythromycin quinupristin/ dalfopristin	methylprednisolone	allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodoneoral contraceptives

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Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics nafcillin rifampin	Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin	Other Drugs / Dietary Supplements bosentan octreotide orlistat St. John’s Wort sulfinpyrazone terbinafine ticlopidine

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Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
boceprevir	↔	No dose adjustment required for ISENTRESS or boceprevir.
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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DRUG INTERACTIONS

CNS depressants: Enhanced CNS-depressant effects with combination use. Use with alcohol causes additive psychomotor impairment (7.1) Imipramine: Decreased alertness observed with combination use. (7.1) Chlorpromazine:Impaired alertness and psychomotor performance observed with combination use (7.1) Rifampin: Combination use decreases exposure to and effects of zolpidem (7.2) Ketoconazole: Combination use increases exposure to and effect of zolpidem (7.2)

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration		Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen		Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine -associated adverse events.
Fosamprenavir	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/ 133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potentialdecrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Substance	Average Duration of Effect
Anti-thyroid drugs e.g., carbimazole, propylthiouracil	5 days
Natural or synthetic thyroid hormone e.g., thyroxine tri-iodothyronine	4 weeks 2 weeks
Iodine-containing medications e.g., amiodarone expectorants, vitamins	4 weeks 2 weeks
Topical iodide	1-9 months
X-ray contrast agents iodine-containing agents	Up to 1 year
Other drugs anticoagulants, antihistamines corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium	1 week 1 week 1 week 1-2 weeks 4 weeks

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicityfrom methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkanizing Agents	Decreased plasma salicylate levels.

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparintreated patients.
Pyrazinamide	Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased T₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone, ketone bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name	Clinical Comment

Alpha 1-adrenoreceptor antagonist: alfuzosin	Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics: amiodarone, quinidine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial: rifampin	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products: St. John's wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
PDE5 inhibitor: sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension]	A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Proton Pump Inhibitors	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics: midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.

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Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine	↑ nelfinavir ↓ delavirdine
nevirapine	↓ nelfinavir (C_min)
Nucleoside Reverse Transcriptase Inhibitor: didanosine		It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Protease Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir	↑ nelfinavir ↑ indinavir
ritonavir	↑ nelfinavir
saquinavir	↑ saquinavir
Other Agents
Anti-coagulant: warfarin	warfarin	Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
Anti-convulsants:		May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine phenobarbital	↓ nelfinavir
Anti-convulsant:		Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin	↓ phenytoin
Anti-depressant: trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-gout colchicine	↑ colchicine	Treatment of gout flares– coadministration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares– coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT.
Anti-Mycobacterial:		It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)
Endothelin receptor antagonists: bosentan	↑ bosentan	Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor:		Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin	↑ atorvastatin
rosuvastatin	↑ rosuvastatin
Immuno-suppressants:		Plasma concentrations may be increased by VIRACEPT.
cyclosporine tacrolimus sirolimus	↑ immuno-suppressants	Plasma concentrations may be increased by VIRACEPT.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Macrolide Antibiotic: azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Narcotic Analgesic:		Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone	↓ methadone
Oral Contraceptive:		Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol	↓ ethinyl estradiol
PDE5 Inhibitors: sildenafil vardenafil tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease,57% decrease]
Phenobarbital	100-150	600-1800	14% increase[CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease,51% decrease]
Phenytoin	250-500	600-1800>1200-2400	nc up to 40% increase [CI: 12% increase,60% increase]	30% decrease [CI: 3% decrease,48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease,40% decrease]

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cation or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agent	Carefully monitor blood glucose (5.11, 7.3)

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AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-Containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport — but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin	melphalan	azapropazon	cimetidine
gentamicin		colchicine	ranitidine
tobramycin	Antifungals	diclofenac
vancomycin	amphotericin B	naproxen	Immunosuppressives
trimethoprim with sulfamethoxazole	ketoconazole	sulindac	tacrolimus

			Other Drugs
			fibric acid derivatives
			(e.g.,bezafibrate, fenofibrate) methotrexate

Table name:

Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/		colchicine
		dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

Table name:

Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		St. John's Wort
		terbinafine
		ticlopidine

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name	Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,^a rifampin^a	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort ( hypericum perforatum)	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

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Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Delavirdine or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Amprenavir	↑Amprenavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Didanosine^a	↓Delavirdine↓Didanosine	Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
Indinavir^a	↑Indinavir	A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir	↑Lopinavir↑Ritonavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavir^a	↑Nelfinavir↓Delavirdine	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. (See CLINICAL PHARMACOLOGY: Tables 1 and 2.)
Ritonavir	↑Ritonavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavir^a	↑Saquinavir	A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
Other Agents
Acid blockers: Antacids^a	↓Delavirdine	Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Acid blockers: Antacids^a	↓Delavirdine
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine	↓Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole	↓Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines	↑Amphetamines	Use with caution.
Antidepressant: Trazodone	↑Trazodone	Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered.
Antiarrhythmics: Bepridil	↑Antiarrhythmics	Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Amiodarone,lidocaine (systemic), quinidine, flecainide, propafenone		Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin	↑Warfarin	It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycin^a	↑Clarithromycin	When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be reduced by 75%.
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil	↑Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Delavirdine	Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil	↑Sildenafil	Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin	↑Atorvastatin ↑Cerivastatin↑Fluvastatin	Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone	↑Fluticasone	Concomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Narcotic analgesic: Methadone	↑Methadone	Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol	↑Ethinyl estradiol	Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	diltiazem	medroxyprogesterone	roxithromycin
systemic and inhaled	dirithromycin	methylprednisolone	sorbitol
amoxicillin	enflurane	metronidazole	(purgative doses
ampicillin,	famotidine	metoprolol	do not inhibit
with or without	felodipine	nadolol	theophylline
sulbactam	finasteride	nifedipine	absorption)
atenolol	hydrocortisone	nizatidine	sucralfate
azithromycin	isoflurane	norfloxacin	terbutaline, systemic
caffeine,	isoniazid	ofloxacin	terfenadine
dietary ingestion	isradipine	omeprazole	tetracycline
cefaclor	influenza vaccine	prednisone,	tocainide
co-trimoxazole	ketoconazole	prednisolone
(trimethoprim and	lomefloxacin	ranitidine
sulfamethoxazole)	mebendazole	rifabutin

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Drug	Description of Interaction
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decrease tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants	Increased bleeding
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
Drug	Description of Interaction
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level
III. Drugs with complicated interactions with salicylates:
Drug	Description of Interaction
Heparin	Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited
The following alterations of laboratory tests have been reported during salicylate therapy⁶:
Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2 - 5 g qd)
5 Hydroxyindole Acetic Acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling
17-OH Corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With Theophylline*
albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole	lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide
* Refer to PRECAUTIONS , Drug Interactions for information regarding table.

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg. ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name	Clinical Comment

Antiarrhythmics: amiodarone, quinidine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial: rifampin	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products: St. John's wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Proton Pump Inhibitors	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics: midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.

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Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV-Antiviral Agents
Protease Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir	↑ nelfinavir ↑ indinavir
ritonavir	↑ nelfinavir
saquinavir	↑ saquinavir
Non-nucleoside Reverse Transcriptase Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine	↑ nelfinavir ↓ delavirdine
nevirapine	↓ nelfinavir (C_min)
Nucleoside Reverse Transcriptase Inhibitor: didanosine		It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Other Agents
Anti-Convulsants:		May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine phenobarbital	↓ nelfinavir
Anti-Convulsant:		Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin	↓ phenytoin
Anti-Mycobacterial:		It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)
PDE5 Inhibitors: sildenafil vardenafil tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. If concomitant use of PDE5 inhibitors and VIRACEPT is required, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended.

HMG-CoA Reductase Inhibitor:		Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin	↑ atorvastatin
rosuvastatin	↑ rosuvastatin
Immuno-suppressants:		Plasma concentrations may be increased by VIRACEPT.
cyclosporine tacrolimus sirolimus	↑ immuno-suppressants	Plasma concentrations may be increased by VIRACEPT.
Narcotic Analgesic:		Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone	↓ methadone
Oral Contraceptive:		Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol	↓ ethinyl estradiol
Macrolide Antibiotic: azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Inhaled/nasal steroid: Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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DRUG	EFFECT
Monoamine Oxidase (MAO) Inhibitors	Hypertension

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazaepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Telaprevir^a	LEXIVA/ritonavir: ↓Amprenavir ↓Telaprevir	Coadministration of LEXIVA/ritonavir and telaprevir is not recommended.
HCV protease inhibitor: Boceprevir	LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted)	Coadministration of LEXIVA/ritonavir and boceprevir is not recommended. A pharmacokinetic interaction has been reported between boceprevir and some HIV protease inhibitors in combination with ritonavir, leading to decreased HIV protease inhibitor concentrations and, in some cases, decreased boceprevir concentrations.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine^a	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir^a	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir^a, nelfinavir^a	LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir^a	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir^a	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravir^a	LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV CCR5 co-receptor antagonist: Maraviroc^a	LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc	No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole^a, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine	↑Colchicine	Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutin^a	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan	↑Bosentan	Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatin^a	↑Atorvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol	↑Salmeterol	Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindrone^a	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. ^a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): •Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. •The following dose adjustments are recommended for use of tadalafil (ADCIRCA^®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours. Use with increased monitoring for adverse events.
Proton pump inhibitors: Esomeprazole^a, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety(Risperidone + 9- Hydroxy-Risperidone (Ratio*)		Risperidone Dose Recommendation
*Change relative to reference
	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure

diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice

hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

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edema
hereditary coumarin resistance
hyperlipemia

hypothyroidism
nephrotic syndrome

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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blood dyscrasias - see cancer collagen vascular disease congestive heart failure
CONTRAINDICATIONS

diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice

hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

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edema hereditary coumarin resistance hyperlipemia

hypothyroidism nephrotic syndrome

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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Table 3. Selected Drugs that altered or are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by ONMELThis list in not all-inclusive.
Drug plasma concentration increased by itraconazole
Antiarrhythmics	digoxin, dofetilide, quinidine, disopyramide
Anticonvulsants	carbamazepine
Anti-HIV Agents	indinavir, ritonavir, saquinavir, maraviroc
Antineoplastics	busulfan, docetaxel, vinca alkaloids
Antipsychotics	pimozide
Benzodiazepines	alprazolam, diazepam, midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers	dihydropyridines (including nisoldipine and felodipine), verapamil
Gastrointestinal Motility Agents	cisapride
HMG CoA-Reductase Inhibitors	atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants	Cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics	oral hypoglycemics (repaglinide)
Opiate Analgesics	fentanyl, levacetylmethadol (levomethadyl), methadone
Polyene Antifungals	amphotericin B
Other	ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide

Decrease plasma concentration of itraconazole
Anticonvulsants	carbamazepine, phenobarbital, phenytoin
Anti-HIV Agents	nevirapine, efavirenz
Antimycobacterials	isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers	antacids, H₂-receptor antagonists, proton pump inhibitors

Increase plasma concentration of itraconazole
Macrolide Antibiotics	clarithromycin, erythromycin
Anti-HIV Agents	indinavir, ritonavir

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Table 4. Selected Drugs that are contraindicated for use with itraconazoleThis list is not all-inclusive.
Antipsychotics	pimozide
Antiarrhythmics	dofetilide, quinidine
Benzodiazepines	oral midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers	Nisoldipine, felodipine
Ergot Alkaloids	dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine)
Gastrointestinal Motility Agents	cisapride
HMG CoA-Reductase Inhibitors	lovastatin, simvastatin
Opiate Analgesics	levacetylmethadol (levomethadyl), methadone

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

Table name:

Salmonella/Microsome Test (Negative)

E. coli DNA Repair Assay (Negative)

Mouse Lymphoma Cell Forward Mutation Assay (Positive)

Chinese Hamster V₇₉Cell HGPRT Test (Negative)

Syrian Hamster Embryo Cell Transformation Assay (Negative)

Saccharomyces cerevisiae Point Mutation Assay (Negative)

Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)

Rat Hepatocyte DNA Repair Assay (Positive)

Table name:

Rat Hepatocyte DNA Repair Assay

Micronucleus Test (Mice)

Dominant Lethal Test (Mice)

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
NC = Less than 10% change in plasma concentration. NE = Not Evaluated.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 8: Established Drug Interactions with Didanosine
Drug	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a The dosing recommendation for coadministration of didanosine delayed-release capsules and tenofovir disoproxil fumarate with respect to meal consumption differs from that of didanosine. See the complete prescribing information for didanosine delayed-release capsules.
ciprofloxacin	↓ ciprofloxacin concentration	Administer didanosine at least 2 hours after or 6 hours before ciprofloxacin.
delavirdine	↓ delavirdine concentration	Administer didanosine 1 hour after delavirdine.
ganciclovir	↓ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
indinavir	↓ indinavir concentration	Administer didanosine 1 hour after indinavir.
methadone	↓ didanosine concentration	Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load.
nelfinavir	↓ No interacion 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine.
tenofovir disoproxil fumarate	↓ didanosine concentration	A dose reduction of didanosine to the following dosage once daily is recommended.^a 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Didanosine and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, didanosine should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 9: Predicted Drug Interactions with Didanosine
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)]. ^b [See Warnings and Precautions (5.6).]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution^b
Antacids containing magnesium or aluminum	↑ side effects associated with antacid components	Use caution with Didanosine Pediatric Powder for Oral Solution
Azole antifungals	↓ ketoconazole or Itraconazole concentration	Administer drugs such as ketoconazole or itraconazole at least 2 hours before didanosine.
Quinolone antibiotics (see also ciprofloxacin in Table 8)	↓ quinolone concentration	Consult package insert of the quinolone.
Tetracycline antibiotics	↓ antibiotic concentration	Consult package insert of the tetracycline.

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral Contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levelsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
Opioids	Cross-tolerance and mutual potentiation
Naltrexone	Oral THC effects were enhanced by opioid receptor blockade.
Alcohol	Increase in the positive subjective mood effects of smoked marijuana

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*

* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	amoxicillin
ampicillin, with or without sulbactam	atenolol
azithromycin	caffeine, dietary ingestion
cefaclor	co-trimoxizole (trimethoprim and sulfamethoxazole)
diltiazem	dirithromycin
enflurane	famotidine
felodipine	finasteride
hydrocortisone	isoflurane
isoniazid	isradipine
influenza vaccine	ketoconazole
lomefloxacin	mebendazole
medroxyprogesterone	methylprednisolone
metronidazole	metoprolol
nadolol	nifedipine
nizatidine	norfloxacin
ofloxacin	omeprazole
prednisone, prednisolone	ranitidine
rifabutin	roxithromycin
sorbitol (purgative doses do not inhibit theophylline absorption)	sucralfate
terfenadine	terbutaline, systemic
tocainide	tetracycline

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Table 2: Drug-Thyroidal Axis Interactions
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Drug or Drug Class
Dopamine / Dopamine Agonists		Glucocorticoids		Octreotide
Effect - Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥1 μg/kg/min); Glucocorticoids (hydrocortisone≥100 mg/day or equivalent); Octreotide ( >100 μg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Drug or Drug Class
Aminoglutethimide Amiodarone		Iodide (including iodine-containing Radiographic contrast agents) Lithium		Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide
Effect - Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Drug or Drug Class
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
Effect - Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Drug or Drug Class
Antacids - Aluminum & Magnesium Hydroxides - Simethicone		Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate		Cation Exchange Resins - Kayexalate Ferrous Sulfate Sucralfate
Effect - Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives		Estrogens (oral) Heroin / Methadone 5-Fluorouracil		Mitotane Tamoxifen
Drugs that may decrease serum TBG concentration
Androgens / Anabolic Steroids			Glucocorticoids
Asparaginase			Slow Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Drug or Drug Class
Furosemide ( > 80 mg IV) Heparin Hydantoins			Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
Effect - Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Drug or Drug Class
Carbamazepine	Hydantoins		Phenobarbital		Rifampin
Effect - Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Drug or Drug Class
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day)			Glucocorticoids - (e.g., Dexamethasone ≥4 mg/day) Propylthiouracil (PTU)
Effect - Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Drug or Drug Class
Anticoagulants (oral)
- Coumarin Derivatives			- Indandione Derivatives
Effect - Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Drug or Drug Class
Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline)			- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
Effect - Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Drug or Drug Class
Antidiabetic Agents - Biguanides		- Meglitinides - Thiazolidinediones		- Sulfonylureas - Insulin
Effect - Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Drug or Drug Class
Cardiac Glycosides
Effect - Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Drug or Drug Class
Cytokines		- Interferon-α		- Interleukin-2
Effect - Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Drug or Drug Class
Growth Hormones		- Somatrem		- Somatropin
Effect - Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Drug or Drug Class
Ketamine
Effect - Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Drug or Drug Class
Methylxanthine Bronchodilators - (e.g., Theophylline)
Effect - Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Drug or Drug Class
Radiographic Agents
Effect - Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Drug or Drug Class
Sympathomimetics
Effect - Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Drug or Drug Class
Chloral Hydrate Diazepam Ethionamide Lovastatin		Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium		Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
Effect - These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaled	felodipinefinasteride	nizatidinenorfloxacin
amoxicillin	hydrocortisone	ofloxacin
ampicillin, with or without sulbactam	isofluraneisoniazid	omeprazoleprednisone, prednisolone
atenolol	isradipine	ranitidine
azithromycin	influenza vaccine	rifabutin
caffeine, dietary ingestion	ketoconazolelomefloxacin	roxithromycinsorbitol
cefaclor	mebendazole	(purgative doses do not
co-trimoxazole (trimethoprim and sulfamethoxazole)	medroxyprogesteronemethylprednisolone	inhibit theophylline absorption)
diltiazem	metronidazole	sucralfate
dirithromycin	metoprolol	terbutaline, systemic
enflurane	nadolol	terfenadine
famotidine	nifedipine	tetracycline
		tocainide
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Drug	Interaction
Valproic acid	Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects (7.1)
Probenecid	Reduces renal clearance of doripenem, resulting in increased doripenem concentrations (7.2, 12.3)
Drugs metabolized by cytochrome P450 enzymes	Doripenem neither inhibits nor induces major cytochrome P450 enzymes (12.3)

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine gluronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 5: AED Drug Interactions with Oxcarbazepine
¹nc denotes a mean change of less than 10%
²Pediatrics
³Mean increase in adults at high doses of immediate-release oxcarbazepine
AED Coadministered (daily dose)	IR- Oxcarbazepine (daily dose)	Influence of IR- Oxcarbazepine on AED Concentration Mean Change [90% Confidence Interval]	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)	Recommendation
Carbamazepine (400 – 2000 mg)	900 mg	nc1	40% decrease [CI: 17% decrease, 57% decrease]	Consider initiating Oxtellar XR™ at a higher dose. Monitor and titrate dose to desired clinical effect (see 2.6)
Phenobarbital (100 – 150 mg)	600 – 1800 mg	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin (250 – 500 mg)	600 – 1800 >1200-2400	nc1,2 up to 40% increase3 [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic Acid (400 – 2800 mg)	600-1800	nc1	18% decrease [CI: 13% decrease, 40% decrease]	Monitor. Dose adjustment of Oxtellar XR™ may not be needed.

Table name:

^aDrugs That May Increase Tacrolimus Blood Concentrations
a) This table is not all inclusive.
b) In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients.
c) Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers.
Calcium	Antifungal	Macrolide
Channel Blockers	Agents	Antibiotics
diltiazem	clotrimazole	clarithromycin
nicardipine	fluconazole	erythromycin
nifedipine	itraconazole	troleandomycin
verapamil	ketoconazole^b voriconazole
Gastrointestinal	Other
Prokinetic Agents	Drugs
cisapride	bromocriptine
metoclopramide	chloramphenicol
	cimetidine
	cyclosporine
	danazol
	ethinyl estradiol
	methylprednisolone
	lansoprazole^c
	omeprazole
	protease inhibitors
	nefazodone
	magnesium-aluminum-hydroxide

Table name:

^aDrugs That May Decrease Tacrolimus Blood Concentrations
a) This table is not all inclusive.
Anticonvulsants	Antimicrobials
carbamazepine	rifabutin
phenobarbital	caspofungin
phenytoin	rifampin
Herbal Preparations	Other Drugs
St. John’s Wort	sirolimus

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , Ieading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%

Ketoconazole (400 mg once daily)	+135%	+164%

Table name:

DRUG	DISCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding

Table name:

DRUG	DISCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying agents	Increases plasma salicylate levels.
Alkcanizing agents	Decreased plasma salicylate levels.

Table name:

DRUG	DISCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and inteferes with hemostasis in heparin treated patients.
Pyrazinamide	Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

Table name:

Table 11: Effect of Other Drugs on Voriconazole Pharmacokinetics
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg Q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy subjects, and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400mg Q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100mg Q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 12: Effect of Voriconazole on Pharmacokinetics of Other Drugs
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400 mg Q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ
Low-dose Ritonavir (100mg Q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary (see CLINICAL PHARMACOLOGY - Drug Interactions).
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with VFEND Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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May Require a Decrease in Dose at Cessation of Smoking	Possible Mechanism
Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline	Deinduction of hepatic enzymes on smoking cessation.
Insulin	Increase of subcutaneous insulin absorption with smoking cessation.
Adrenergic antagonists (e.g. prazosin, labetalol)	Decrease in circulating catecholamines with smoking cessation.
May Require an Increase in Dose at Cessation of Smoking	Possible Mechanism
Adrenergic agonists (e.g. isoproterenol, phenylephrine)	Decrease in circulating catecholamines with smoking cessation.

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Substance	Average Duration of Effect
Anti-thyroid drugs e.g., carbimazole, propylthiouracil	5 days
Natural or synthetic thyroid hormone e.g., thyroxine tri-iodothyronine	4 weeks 2 weeks
Iodine-containing medications e.g., amiodarone expectorants, vitamins	4 weeks 2 weeks
Topical iodide	1-9 months
X-ray contrast agents iodine-containing agents	Up to 1 year
Other drugs anticoagulants, antihistamines corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium	1 week 1 week 1 week 1-2 weeks 4 weeks

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Table 11:Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 14 and 15]
Concomitant Drug Class: Drug Name	Effect on Concentration of Darunavir or Concomitant Drug	Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine	↔ darunavir ↔ didanosine	Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)	↑ darunavir ↑ indinavir	The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir	↓ darunavir ↔ lopinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir	↓ darunavir ↔ saquinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc	↑ maraviroc	Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics: bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone	↑ antiarrhythmics	Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin	↑ digoxin	The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant: warfarin	↓ warfarin ↔ darunavir	Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant: carbamazepine	↔ darunavir ↑ carbamazepine	The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant: phenobarbital, phenytoin	↔ darunavir ↓ phenytoin ↓ phenobarbital	Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant: trazodone, desipramine	↑ trazodone ↑ desipramine	Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective: clarithromycin	↔ darunavir ↑ clarithromycin	No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals: ketoconazole, itraconazole, voriconazole	↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied)	Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
		Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
		Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimalarials: artemether/lumefantrine	↓ artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir	The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation.
Antimycobacterial: rifabutin	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin	Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel Blockers: felodipine, nifedipine, nicardipine	↑ calcium channel blockers	Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Systemic: dexamethasone	↓ darunavir	Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents: NS3-4A protease inhibitors: boceprevir telaprevir	↓ darunavir ↓ boceprevir ↓ telaprevir	Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin	↑ pravastatin ↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence: methadone, buprenorphine, buprenorphine/naloxone	↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite)	No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics: risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone	↓ ethinyl estradiol ↓ norethindrone	Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors: sildenafil, vardenafil, tadalafil	↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir)	Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine	↔ darunavir ↓ sertraline ↓ paroxetine	If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.

Table name:

Mean (SD) Pharmacokinetic Parameters in Healthy Young Subjects (n=15)
	Mean (±SD)
Bioavailability	63% (34 to 108%)Range
Clearance (mL/min)	165 (55)
Volume of Distribution (L)	76 (14)
Half-Life (hours)	6.2 (2.1)

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Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5 mg/day in Older Men
	Mean (± SD)
	45 to 60 years old (n=12)	≥70 years old (n=12)
AUC (ng·hr/mL)	389 (98)	463 (186)
Peak Concentration (ng/mL)	46.2 (8.7)	48.4 (14.7)
Time to Peak (hours)	1.8 (0.7)	1.8 (0.6)
Half-Life (hours)First-dose values; all other parameters are last-dose values	6.0 (1.5)	8.2 (2.5)

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Table 5 Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Boceprevir or Concomitant Drug	Recommendations
Antiarrhythmics: amiodarone, bepridil, propafenone, quinidine	↑ antiarrhythmics	Coadministration with VICTRELIS has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with VICTRELIS.
digoxin	↑ digoxin	Digoxin concentrations increased when administered with VICTRELIS [see Clinical Pharmacology (12.3)]. Measure serum digoxin concentrations before initiating VICTRELIS. Continue monitoring digoxin concentrations; consult the digoxin prescribing information for information on titrating the digoxin dose.
Anticoagulant: warfarin	↑ or ↓ warfarin	Concentrations of warfarin may be altered when co-administered with VICTRELIS. Monitor INR closely.
Antidepressants: trazodone, desipramine	↑ trazodone ↑ desipramine	Plasma concentrations of trazodone and desipramine may increase when administered with VICTRELIS, resulting in adverse events such as dizziness, hypotension and syncope. Use with caution and consider a lower dose of trazodone or desipramine.
escitalopram	↓escitalopram	Exposure of escitalopram was slightly decreased when coadministered with VICTRELIS. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with VICTRELIS.
Antifungals: ketoconazoleThese combinations have been studied; see Clinical Pharmacology (12.3) for magnitude of interaction., itraconazole, posaconazole, voriconazole	↑ boceprevir ↑ itraconazole ↑ ketoconazole ↑ posaconazole ↑ voriconazole	Plasma concentrations of ketoconazole, itraconazole, voriconazole or posaconazole may be increased with VICTRELIS. When coadministration is required, doses of ketoconazole and itraconazole should not exceed 200 mg/day.
Anti-gout: colchicine	↑ colchicine	Significant increases in colchicine levels are expected; fatal colchicine toxicity has been reported with other strong CYP3A4 inhibitors. Patients with renal or hepatic impairment should not be given colchicine with VICTRELIS. Treatment of gout flares (during treatment with VICTRELIS): 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares (during treatment with VICTRELIS): If the original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, reduce the dose to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF) (during treatment with VICTRELIS): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective: clarithromycin	↑ clarithromycin	Concentrations of clarithromycin may be increased with VICTRELIS; however, no dosage adjustment is necessary for patients with normal renal function.
Antimycobacterial: rifabutin	↓ boceprevir ↑ rifabutin	Increases in rifabutin exposure are anticipated, while exposure of boceprevir may be decreased. Doses have not been established for the 2 drugs when used in combination. Concomitant use is not recommended.
Calcium Channel Blockers, dihydropyridine: felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Plasma concentrations of dihydropyridine calcium channel blockers may increase when administered with VICTRELIS. Caution is warranted and clinical monitoring is recommended.
Corticosteroid, systemic: dexamethasone	↓ boceprevir	Coadministration of VICTRELIS with CYP3A4/5 inducers may decrease plasma concentrations of boceprevir, which may result in loss of therapeutic effect. Therefore, this combination should be avoided if possible and used with caution if necessary.
prednisone	↑ prednisone	Concentrations of prednisone and its active metabolite, prednisolone, increased when administered with VICTRELIS [see Clinical Pharmacology (12.3)]. No dose adjustment of prednisone is necessary when co-administered with VICTRELIS. Patients receiving prednisone and VICTRELIS should be monitored appropriately.
Corticosteroid, inhaled: budesonide, fluticasone	↑ budesonide ↑ fluticasone	Concomitant use of inhaled budesonide or fluticasone with VICTRELIS may result in increased plasma concentrations of budesonide or fluticasone, resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for extended durations.
Endothelin Receptor Antagonist: bosentan	↑ bosentan	Concentrations of bosentan may be increased when coadministered with VICTRELIS. Use with caution and monitor closely.
HIV Integrase Inhibitor: raltegravir	↔ raltegravir	No dose adjustment required for VICTRELIS or raltegravir.
HIV Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when VICTRELIS was coadministered with efavirenz, which may result in loss of therapeutic effect. Avoid combination.
etravirine	↓ etravirine	Concentrations of etravirine decreased when coadministered with VICTRELIS. The clinical significance of the reductions in etravirine pharmacokinetic parameters has not been directly assessed.
HIV Protease Inhibitors: atazanavir/ritonavir	↓ atazanavir ↓ ritonavir	Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended.
darunavir/ritonavir	↓ darunavir ↓ ritonavir ↓ boceprevir	Concomitant administration of boceprevir and darunavir/ritonavir resulted in reduced steady-state exposures to boceprevir, darunavir and ritonavir. Coadministration of darunavir/ritonavir and boceprevir is not recommended.
lopinavir/ritonavir	↓ lopinavir ↓ ritonavir ↓ boceprevir	Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir. Coadministration of lopinavir/ritonavir and boceprevir is not recommended.
ritonavir	↓ boceprevir	When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased.
HMG-CoA Reductase Inhibitors: atorvastatin	↑ atorvastatin	Exposure to atorvastatin was increased when administered with VICTRELIS. Use the lowest effective dose of atorvastatin, but do not exceed a daily dose of 40 mg when coadministered with VICTRELIS.
pravastatin	↑ pravastatin	Concomitant administration of pravastatin with VICTRELIS increased exposure to pravastatin. Treatment with pravastatin can be initiated at the recommended dose when coadministered with VICTRELIS. Close clinical monitoring is warranted.
Immunosuppressants: cyclosporine tacrolimus sirolimus	↑cyclosporine	Dose adjustments of cyclosporine should be anticipated when administered with VICTRELIS and should be guided by close monitoring of cyclosporine blood concentrations, and frequent assessments of renal function and cyclosporine-related side effects.
	↑tacrolimus	Concomitant administration of VICTRELIS with tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects.
	↑sirolimus	Blood concentrations of sirolimus are expected to increase significantly when administered with VICTRELIS. Close monitoring of sirolimus blood levels is recommended.
Inhaled beta-agonist: salmeterol	↑ salmeterol	Concurrent use of inhaled salmeterol and VICTRELIS is not recommended due to the risk of cardiovascular events associated with salmeterol.
Narcotic Analgesic/Opioid Dependence: methadone	↓ R-methadone	Plasma concentrations of R-methadone decreased when coadministered with VICTRELIS [see Clinical Pharmacology (12.3)]. The observed changes are not considered clinically relevant. No dose adjustment of methadone or VICTRELIS is recommended. Individual patients may require additional titration of their methadone dosage when VICTRELIS is started or stopped to ensure clinical effect of methadone.
buprenorphine/naloxone	↑ buprenorphine/naloxone	Plasma concentrations of buprenorphine and naloxone increased when coadministered with VICTRELIS [see Clinical Pharmacology (12.3)]. The observed changes are not considered clinically relevant. No dose adjustment of buprenorphine/naloxone or VICTRELIS is recommended.
Oral hormonal contraceptives: drospirenone/ethinyl estradiol	↑ drospirenone ↓ ethinyl estradiol	Concentrations of drospirenone increased in the presence of boceprevir. Thus, the use of drospirenone-containing products is contraindicated during treatment with VICTRELIS due to potential for hyperkalemia [see Contraindications (4)].
norethindrone/ethinyl estradiol	↓ ethinyl estradiol ↔ norethindrone	Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone C_max decreased 17% in the presence of boceprevir [see Clinical Pharmacology (12.3)]. Coadministration of VICTRELIS with a combined oral contraceptive containing ethinyl estradiol and at least 1 mg of norethindrone is not likely to alter the effectiveness of this combined oral contraceptive [see Use in Specific Populations (8.1)]. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Increases in PDE5 inhibitor concentrations are expected, and may result in an increase in adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of REVATIO^® (sildenafil) or ADCIRCA^® (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated with VICTRELIS [see Contraindications (4)]. Use of PDE5 inhibitors for erectile dysfunction: Use with caution in combination with VICTRELIS with increased monitoring for PDE5 inhibitor-associated adverse events. Do not exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 24 hours
Proton Pump Inhibitor: omeprazole	↔ omeprazole	No dose adjustment of omeprazole or VICTRELIS is recommended.
Sedative/hypnotics: alprazolam; IV midazolam	↑ midazolam ↑ alprazolam	Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of VICTRELIS. A lower dose of IV midazolam or alprazolam should be considered.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_SS(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

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Interaction Drug	Interaction
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole	Avoid coadministration unless the benefit outweighs the risks (7.6, 7.7, 7.8, 7.9)
Other drugs metabolized by CYP3A4 (tacrolimus, cyclosporine, vinca alkaloids, calcium channel blockers)	Consider dosage adjustment and monitor for adverse effects and toxicity (7.1, 7.10, 7.11)
Digoxin	Monitor digoxin plasma concentrations (7.12)
Fosamprenavir, metoclopramide	Monitor for breakthrough fungal infections (7.6, 7.13)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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DRUG	EFFECT
Monoamine Oxidase (MAO) Inhibitors	Hypertension

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drug		Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).		Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic anti-depressants.		Pressor response increased.
Phenylephrine with ergot alkaloids.		Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.		Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.		Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.		Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.		Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.		Synergistic adrenergic response.

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
Drug	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^aCoadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
ganciclovir	↑ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine- associated toxicity.
methadone	↓ didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxil fumarate	↑ didanosine concentration	A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.^a 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase. ^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules is recommended [see Warnings and Precautions (5.1)]. ^b [See Warnings and Precautions (5.6).]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution.^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution.^b

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Drugs That May Potentiate Renal Dysfunction
Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole	melphalan	azapropazon colchicine diclofenac naproxen sulindac	cimetidine ranitidine
	Antifungals		cimetidine ranitidine
	amphotericin B ketoconazole		Immunosuppressives
			tacrolimus
			Other Drugs
			fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

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Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem nicardipine verapamil	fluconazole itraconazole ketoconazole voriconazole	azithromycin clarithromycin erythromycin quinupristin/ dalfopristin	methylprednisolone	allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodoneoral contraceptives

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Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics nafcillin rifampin	Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin	Other Drugs / Dietary Supplements bosentan octreotide orlistat St. John’s Wort sulfinpyrazone terbinafine ticlopidine

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine AgonistsGlucocorticoidsOctreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min);Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
AminoglutethimideAmiodarone Iodide (including iodine-containing Radiographiccontrast agents)LithiumMethimazolePropylthiouracil (PTU)SulfonamidesTolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
AmiodaroneIodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids- Aluminum &Magnesium Hydroxides- SimethiconeBile Acid Sequestrants- Cholestyramine- ColestipolCalcium CarbonateCation Exchange Resins- KayexalateFerrous SulfateOrlistatSucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport – but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
ClofibrateEstrogen-containing oral contraceptives Estrogens (oral)Heroin/Methadone5-FluorouracilMitotaneTamoxifen	Androgens/Anabolic SteroidsAsparaginaseGlucocorticoidsSlow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)HeparinHydantoinsNon-Steroidal Anti-Inflammatory Drugs- Fenamates- PhenylbutazoneSalicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄.Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
CarbamazepineHydantoinsPhenobarbitalRifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
AmiodaroneBeta-adrenergic antagonists- (e.g., Propranolol> 160 mg/day)Glucocorticoids- (e.g., Dexamethasone≥ 4 mg/day)Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)- Coumarin Derivatives- Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin timeshould be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants- Tricyclics (e.g., Amitriptyline)- Tetracyclics (e.g., Maprotiline)- Selective SerotoninReuptake Inhibitors(SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline inpatients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents- Biguanides- Meglitinides- Sulfonylureas- Thiazolidediones- Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines- Interferon-α- Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients, and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and –γ have not been reported to cause thyroid dysfunction.
Growth Hormones- Somatrem- Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators- (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral HydrateDiazepamEthionamideLovastatinMetoclopramide6-MercaptopurineNitroprussidePara-aminosalicylate sodiumPerphenazineResorcinol (excessivetopical use)Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓=Decreased (induces lamotrigine glucuronidation). ↑=Increased (inhibits lamotrigine glucuronidation). ?=Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure

diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice

hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

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edema
hereditary coumarin resistance
hyperlipemia

hypothyroidism
nephrotic syndrome

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
Caffeine,	nifedipine
dietary ingestion	nizatidine
cefactor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid terbutaline,	systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 1 Changes in Desloratadine and 3-Hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Volunteers
	Desloratadine		3-Hydroxydesloratadine
	C_max	AUC 0–24 hrs	C_max	AUC 0–24 hrs
Erythromycin (500 mg Q8h)	+24%	+14%	+43%	+40%
Ketoconazole (200 mg Q12h)	+45%	+39%	+43%	+72%
Azithromycin (500 mg day 1, 250 mg QD × 4 days)	+15%	+5%	+15%	+4%
Fluoxetine (20 mg QD)	+15%	+0%	+17%	+13%
Cimetidine (600 mg Q12h)	+12%	+19%	-11%	-3%

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Rifabutin Interaction StudiesND - No data
AUC - Area under the Concentration vs. Time Curve
Cmax - Maximum serum concentration
Coadministered Drugs	Effect on Rifabutin	Effect on Coadministered Drug	Comments
ANTIVIRALS
Amprenavir	2.9-fold ↑ AUC, 2.2-fold ↑ Cmax	No significant change in kinetics.	A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted.
Delavirdine	ND	Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM)	Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h.
Didanosine	No significant change in kinetics.	No significant change in kinetics at steady state.
Fosamprenavir/ritonavir	64% ↑ AUC - Drug plus active metabolite	35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir)	Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir
Indinavir	204% ↑ in AUC	32%↓ in AUC
Lopinavir/ritonavir	5.7-fold ↑ AUC, 3.4 fold ↑ Cmax	No significant change in lopinavir kinetics.	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary.
Saquinavir	ND	40% ↓ in AUC
Ritonavir	4 fold increase in AUC, 2.5 fold increase in Cmax	ND	In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered.
Tipranavir/ritonavir[133]	2.9-fold ↑ AUC, 1.7-fold ↑ Cmax	No significant change in tipranavir kinetics.	Therapeutic drug monitoring of rifabutin is recommended.
Zidovudine	No significant change in kinetics.	Approximately 32%↓ in Cmax and AUC	A large controlled clinical study has shown that these changes are of no clinical relevance.
ANTIFUNGALS
ANTIFUNGALS	82% ↑ in AUC	No significant change in steady-state plasma concentrations
Itraconazole	ND	70% to 75% ↓ in Cmax and AUC	One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole.
Posaconazole	31%↑ Cmax, 72%↑ AUC	43%↓ Cmax, 49%↓ AUC	If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration.
Voriconazole	195%↑ Cmax, 331%↑ AUC - voriconazole dosed at 400 mg twice daily	Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily.	If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone	ND	Approximately 27% to 40% ↓ in AUC	Study conducted in HIV infected patients (rapid and slow acetylators).
Sulfamethoxazole-Trimethoprim	No significant change in Cmax and AUC	Approximately 15% to 20% ↓ in AUC	In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant.
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin	No PK interaction	No PK interaction
Clarithromycin	Approximately 77% ↑ in AUC	Approximately 50%↓ in AUC	Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin
ANTI-TB (Tuberculosis)
Ethambutol	ND	No significant change in AUC or Cmax
Isoniazid	ND	Pharmacokinetics not affected
Pyrazinamide	ND	ND	Study data being evaluated.
OTHER
Methadone	ND	No significant effect	No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated.
Ethinylestradiol	ND	35%↓ AUC 20%↓ Cmax	Patients should be advised to use other methods of contraception.
Norethindrone	ND	46%↓ AUC	Patients should be advised to use other methods of contraception.
Tacrolimus	ND	ND	Authors report that rifabutin decreases tacrolimus trough blood levels.
Theophylline	ND	No significant change in AUC or Cmax compared with baseline.

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Table 5 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class: Drug Name	Effect on Concentration of Saquinavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: DelavirdineINVIRASE/ritonavir interaction has not been evaluated.	↑ Saquinavir Effect on delavirdine is not well established	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor: EfavirenzSee CLINICAL PHARMACOLOGY: Pharmacokinetics , Table 2 and Table 3 for magnitude of interactions., nevirapine	↓ Saquinavir ↔ Efavirenz	Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir (1000/100 mg bid) with respect to safety and efficacy have not been established.
HIV protease inhibitor: Atazanavir	INVIRASE/ritonavir ↑ Saquinavir ↑ Ritonavir ↔ Atazanavir	Appropriate dosing recommendations for this combination, with respect to efficacy and safety, have not been established. When 1600 mg INVIRASE/100 mg ritonavir and 300 mg atazanavir were coadministered, plasma concentrations of saquinavir and ritonavir were increased.
HIV protease inhibitor: Indinavir	↑ Saquinavir Effect on indinavir is not well established	Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV protease inhibitor: Lopinavir/ritonavir (coformulated capsule)	↔ Saquinavir ↔ Lopinavir ↓ Ritonavir	Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid.
HIV protease inhibitor: Tipranavir/ritonavir	↓ Saquinavir	Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV fusion inhibitor: Enfuvirtide	Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide	No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
Other Agents
Antiarrhythmics: Lidocaine (systemic)	↑ Antiarrhythmics	Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics given with INVIRASE/ritonavir.
Anticoagulant: Warfarin	↑ Warfarin	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin	↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established	Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-infective: Clarithromycin	↑ Saquinavir ↑ Clarithromycin	Appropriate doses of the combination of clarithromycin and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended: For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungal: Ketoconazole, itraconazole	↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole	Appropriate doses of the combination of ketoconazole or itraconazole and INVIRASE/ritonavir with respect to safety and efficacy have not been established. When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentration of ketoconazole was increased (see Table 2 ). Hence, doses of ketoconazole > 200 mg/day are not recommended.
Antimycobacterial: Rifabutin	↓ Saquinavir ↑ Rifabutin	Appropriate doses of the combination of rifabutin and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑ Benzodiazepines	Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine : Intravenously administered Midazolam	↑ Midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see Contraindications (4)]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers : Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑ Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓ Saquinavir	Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Digitalis Glycosides: Digoxin	↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.	Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir (see WARNINGS ).
Inhaled/nasal steroid: Fluticasone	INVIRASE/ritonavir ↑ Fluticasone	Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS ).
HMG-CoA reductase inhibitors : Atorvastatin, rosuvastatin	↑ Atorvastatin ↑ Rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir (see WARNINGS ).
Immunosuppressants : Cyclosporine, tacrolimus, rapamycin	↑ Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic: Methadone	↓ Methadone	Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.
Oral contraceptives: Ethinyl estradiol	↓ Ethinyl estradiol	Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors): Sildenafil, vardenafil, tadalafil	↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil	Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Antidepressant: Trazodone	↑ Trazodone	Concomitant use of trazodone and INVIRASE/ritonavir may increase plasma concentration of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as INVIRASE/ritonavir, the combination should be used with caution and lower dose of trazodone should be considered.
Tricyclic antidepressants : Amitriptyline, imipramine	↑ Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Proton pump inhibitors: Omeprazole	↑ Saquinavir	When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis.
Herbal Products: St. John's wort (hypericum perforatum)	↓ Saquinavir	Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors (see WARNINGS ).
Garlic Capsules	↓ Saquinavir	Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.

Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposureand there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures .
Fosamprenavir*	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine, Etravirine, Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics:Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*	↓ Clarithromycin↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

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Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

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Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 5: Clarithromycin Tissue Concentrations 2 hours after Dose¹
	¹Mean ± (μg/g)
Tissue	Clarithromycin	Clarithromycin + Omeprazole
Antrum	10.48 ± 2.01 (n = 5)	19.96 ± 4.71 (n = 5)
Fundus	20.81 ± 7.64 (n = 5)	24.25 ± 6.37 (n = 5)
Mucus	4.15 ± 7.74 (n = 4)	39.29 ± 32.79 (n = 4)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

Table name:

Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high Oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI:13% decrease, 40% decrease]

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Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
^a Should be administered at least 4 hours prior to WELCHOL
^b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
^c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
Drugs with a known interaction with colesevelam	Cyclosporine^c, glyburide^a, levothyroxine^a, and oral contraceptives containing ethinyl estradiol and norethindrone^a
Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL	phenytoin^a, warfarin^b
Drugs that do not interact with colesevelam based on in vitro or in vivo testing	cephalexin, ciprofloxacin, digoxin, warfarin^b fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil

Table name:

Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
*nc denotes a mean change of less than 10% †Pediatrics ‡Mean increase in adults at high Oxcarbazepine doses
Carbamazepine	400-2000	900	nc *	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 less then 1200-2400	nc * ^, † up to 40% increase ‡ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc *	18% decrease [CI:13% decrease, 40% decrease]

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
Opioids	Cross-tolerance and mutual potentiation
Naltrexone	Oral THC effects were enhanced by opioid receptor blockade.
Alcohol	Increase in the positive subjective mood effects of smoked marijuana

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety(Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone DoseRecommendation
	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6)Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Donot exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-	Re-evaluate dosing. Donot exceed 8 mg/day
Enzyme (CYP3A/PgP inducers)Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards.Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum and Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkalizing Agents	Decreased plasma salicylate levels.

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2 Effects of Paroxetine on Other Drugs
Concomitant Drug Name	Effect of Paroxetine on Other Drugs	Clinical Recommendations
Thioridazine	Increased plasma concentrations of thioridazine Potential QTc prolongation	Concomitant use of thioridazine and BRISDELLE is contraindicated.
Pimozide	Increased plasma concentrations of pimozide. Potential QTc prolongation	Concomitant use of pimozide and BRISDELLE is contraindicated.
Tamoxifen	Reduced plasma concentrations of active tamoxifen metabolite	Consider avoiding concomitant use of tamoxifen and BRISDELLE.
Tricyclic Antidepressant (TCA) (e.g., Desipramine)	Increased plasma concentrations and elimination half-life	Plasma TCA concentrations may need to be monitored and the dose of TCA may need to be reduced if a TCA is co-administered with BRISDELLE. Monitor tolerability.
Risperidone	Increased plasma concentrations of risperidone	A lower dosage of risperidone may be necessary (see the Full Prescribing Information for risperidone). Monitor tolerability.
Atomoxetine	Increased exposure of atomoxetine	A lower dosage of atomoxetine may be necessary (see Full Prescribing Information for atomoxetine). Monitor tolerability.
Drugs Highly Bound to Plasma Protein (e.g., Warfarin)	Increased free plasma concentrations	The dosage of warfarin may need to be reduced. Monitor tolerability and the International Normalized Ratio.
Digoxin	Decreased plasma concentrations of digoxin	Dosage of digoxin may need to be increased. Monitor digoxin concentrations and clinical effect.
Theophylline	Increased plasma concentrations of theophylline	Dosage of theophylline may need to be decreased. Monitor theophylline concentrations and tolerability.

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Table 3 Effects of Other Drugs on Paroxetine
Concomitant Drug Name	Effect of Concomitant Drug on Paroxetine	Clinical Recommendations
Phenobarbital	Decreased paroxetine exposure
Phenytoin	Decreased paroxetine exposure
Fosamprenavir/ Ritonavir	Decreased plasma concentration of paroxetine	No dose adjustment for BRISDELLE. Monitor clinical effect of BRISDELLE.
Cimetidine	Increased plasma concentration of paroxetine

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Antibiotics	Antineoplastic	Antifungals	Anti- Inflammatory Drugs	Gastrointestinal Agents	Immunosuppressives	Other Drugs
ciprofloxacingentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin	melphalan	amphotericin Bketoconazole	azapropazoncolchicine diclofenacnaproxen sulindac	cimetidine ranitidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
		quinupristin/		colchicine
	voriconazole	dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Antibiotics	Anticonvulsants	Other Drugs/DietarySupplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

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Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 3 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class: Drug Name	Effect on Concentration of Saquinavir or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: DelavirdineINVIRASE/ritonavir interaction has not been evaluated.	↑ Saquinavir Effect on delavirdine is not well established	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor: EfavirenzSee Drug Interactions (7) , Table 5 and Table 6 for magnitude of interactions., nevirapine	↓ Saquinavir ↔ Efavirenz	Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor: Atazanavir	INVIRASE/ritonavir ↑ Saquinavir ↑ Ritonavir ↔ Atazanavir	Atazanavir in combination with INVIRASE/ritonavir should be used with caution. Additive effects on PR interval prolongation may occur with INVIRASE/ritonavir [see Warnings and Precautions (5.2)].
HIV-1 protease inhibitor: Indinavir	↑ Saquinavir Effect on indinavir is not well established	Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV-1 protease inhibitor: Lopinavir/ritonavir (coformulated tablet)	↔ Saquinavir ↔ Lopinavir ↓ Ritonavir	Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid. Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.2, 5.3)].
HIV-1 protease inhibitor: Tipranavir/ritonavir	↓ Saquinavir	Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV-1 fusion inhibitor: Enfuvirtide	Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide	No clinically significant interaction was noted from a study in 12 HIV-1 subjects who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
HIV-1 CCR5 antagonist: Maraviroc	↑ Maraviroc	Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Ibutilide Sotalol		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Anticoagulant: Warfarin	↑ Warfarin	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin	↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established	Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-gout: Colchicine	↑ Colchicine	Treatment of gout flares-coadministration of colchicine in patients on INVIRASE/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Treatment of familial Mediterranean fever (FMF) coadministration of colchicine in patients on INVIRASE/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Prophylaxis of gout-flares-co-administration of colchicine in patients on INVIRASE/ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir.
Anti-infective: Clarithromycin	↑ Saquinavir ↑ Clarithromycin	Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Erythromycin Halofantrine Pentamidine		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Antifungal: Ketoconazole, itraconazole	↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole	When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see Table 3 ). Hence, doses of ketoconazole or itraconazole >200 mg/day are not recommended.
Antimycobacterial: Rifabutin	↔ Saquinavir ↑ Rifabutin ↔ Ritonavir	No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if ritonavir-boosted INVIRASE is administered in combination with rifabutin. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination. Consider monitoring rifabutin concentrations to ensure adequate exposure.
Benzodiazepines : Alprazolam, clorazepate, diazepam, flurazepam	↑ Benzodiazepines	Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine : Intravenously administered Midazolam	↑ Midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see Contraindications (4)]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers : Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑ Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓ Saquinavir	Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations.
Digitalis Glycosides: Digoxin	↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.	Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir.
Endothelin receptor antagonists: Bosentan	↑ Bosentan	Coadministration of bosentan in patients on INVIRASE/ritonavir: In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of INVIRASE/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir. After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Inhaled beta agonist: Salmeterol	↑ Salmeterol	Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	INVIRASE/ritonavir ↑ Fluticasone	Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
HMG-CoA reductase inhibitors : Atorvastatin	↑ Atorvastatin	Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day.
Immunosuppressants : Cyclosporine, tacrolimus, rapamycin	↑ Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic: Methadone	↓ Methadone	Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Neuroleptics: Clozapine Haloperidol Mesoridazine Phenothiazines Thioridazine Ziprasidone		Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Oral contraceptives: Ethinyl estradiol	↓ Ethinyl estradiol	Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors): Sildenafil, vardenafil, tadalafil	↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction.	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with INVIRASE/ritonavir: Coadministration of Adcirca in patients on INVIRASE/ritonavir: In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of INVIRASE/ritonavir in patients on Adcirca: Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Tricyclic antidepressants : Amitriptyline, imipramine	↑ Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Proton pump inhibitors: Omeprazole	↑ Saquinavir	When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.
Herbal Products: St. John's wort (hypericum perforatum)	↓ Saquinavir	Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
Garlic Capsules	↓ Saquinavir	Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
AED Coadministered	AED Concentration	Felbamate Concentration
Phenytoin	↑	↓
Valproate	↑	↔**
Carbamazepine (CBZ) *CBZ epoxide	↓ ↑	↓
Phenobarbital	↑	↓

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine,	nifedipine
dietary ingestion	nizatidine
cefactor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc*	40% decrease
				[CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase	25% decrease
			[CI: 2% increase, 24% increase]	[CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800	nc ^, †	30% decrease
		>1200-2400	up to 40% increase‡	[CI: 3% decrease, 48% decrease]
			[CI: 12% increase, 60% increase]
Valproic acid	400-2800	600-1800	nc	18% decrease
				[CI: 13% decrease, 40% decrease]

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Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis with Atorvastatin (2.3, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations for LIPTRUZET
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir), gemfibrozil	Avoid LIPTRUZET
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary.
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 10/20 mg LIPTRUZET daily.
HIV protease inhibitor (nelfinavir), hepatitis C protease inhibitor (boceprevir)	Do not exceed 10/40 mg LIPTRUZET daily.

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses greater than or equal to 600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20–40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33–100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	medroxyprogesterone
amoxicillin	methylprednisolone
ampicillin, with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine
cefaclor	nizatidine
co-trimoxazole	norfloxacin
(trimethoprim and sulfamethoxazole)	ofloxacin
diltiazem	omeprazole
dirithromycin	prednisone, prednisolone
enflurane	ranitidine
famotidine	rifabutin
felodipine	roxithromycin
finasteride	sorbitol
hydrocortisone	(purgative doses do not inhibit
isoflurane	theophylline absorption)
isoniazid	sucralfate
isradipine	terbutaline, systemic
influenza vaccine	terfenadine
ketoconazole	tetracycline
lomefloxacin	tocainide
mebendazole

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure

diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice

hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

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edema
hereditary coumarin resistance
hyperlipemia

hypothyroidism
nephrotic syndrome

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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Table 4: Clarithromycin Tissue Concentrations 2 hours after DoseMean ± (ug/g)
Tissue	Clarithromycin	Clarithromycin + Omeprazole
Antrum	10.48 ± 2.01 (n=5)	19.96 ± 4.71 (n=5)
Fundus	20.81 ± 7.64 (n=5)	24.25 ± 6.37 (n=5)
Mucus	4.15 ± 7.74 (n=4)	39.29 ± 32.79 (n=4)

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient𕢙s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole

	% Change from Plavix (300 mg/75 mg) alone
Plavix plus	C_max (ng/mL)		AUC		Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
	Day 1	Day 5	Day 1	Day 5AUC at Day 5 is AUC_0–24	Day 1	Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg	↓46%	↓42%	↓45%	↓40%	↓39%	↓21%
Pantoprazole 80 mg	↓24%	↓28%	↓20%	↓14%	↓15%	↓11%

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine gluronidation). ?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not coadminister nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is coadministered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓ Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500 mg/125 mg twice daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533 mg/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 kg to < 15 kg; 11/2.75 mg/kg for those 15 kg to 45 kg; up to a maximum dose of 533 mg/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comment
* see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine. [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir. [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir. [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine vinblastine	↑ anticancer agents	Concentrations of vincristine or vinblastine may be increased when co-administered with lopinavir/ritonavir (KALETRA) resulting in the potential for increased adverse events usually associated with these anticancer agents. Consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir/ritonavir ( KALETRA) is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone. [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Narcotic Analgesic: methadone*	↓ methadone	Dosage of methadone may need to be increased when co-administered with KALETRA.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decease]
Valproic acid	400 to 2800	600 to 1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.

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Table 5: Established Drug Interactions Based on Studies with Didanosine or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine
↑Indicates increase. ↓Indicates decrease.
Drug	Effect	Clinical Comment
ganciclovir	↑didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
methadone	↓didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine.
tenofovir disoproxil fumarate	↑didanosine concentration	A dose reduction of didanosine to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 6: Predicted Drug Interactions with Didanosine
↑ Indicates increase.
Drug or Drug Class	Effect	Clinical Comment
Drugs that may cause pancreatic toxicity	↑risk of pancreatitis	Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)].
Neurotoxic drugs	↑risk of neuropathy	Use with caution.[See Warnings and Precautions (5.5).]

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*Range
Mean (SD) Pharmacokinetic Parameters in Healthy Young Subjects (n=15)
	Mean (± SD)
Bioavailability	63% (34-108%)*
Clearance (mL/min)	165 (55)
Volume of Distribution (L)	76 (14)
Half-Life (hours)	6.2 (2.1)

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*First-dose values; all other parameters are last-dose values
Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5 mg/day in Older Men
	Mean (± SD)
	45 to 60 years old (n=12)	≥70 years old (n=12)
AUC (ng•hr/mL)	389 (98)	463 (186)
Peak Concentration (ng/mL)	46.2 (8.7)	48.4 (14.7)
Time to Peak (hours)	1.8 (0.7)	1.8 (0.6)
Half-Life (hours)*	6 (1.5)	8.2 (2.5)

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
*Change relative to reference

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Table 7 Summary of AED Interactions with Oxcarbazepine
¹ nc denotes a mean change of less than 10% ² Pediatrics ³ Mean increase in adults at high oxcarbazepine doses
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 > 1200 to 2400	^nc ^1,2 ^{up to 40% increase3 [CI: 12% increase, 60% increase]}	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole

	% Change from Plavix (300 mg/75 mg) alone
Plavix plus	Cmax (ng/mL)		AUC		Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
	Day 1	Day 5	Day 1	Day 5AUC at Day 5 is AUC_0-24	Day 1	Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg	↓46%	↓42%	↓45%	↓40%	↓39%	↓21%
Pantoprazole 80 mg	↓24%	↓28%	↓20%	↓14%	↓15%	↓11%

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , ) 2.6 5.1 7.1 7.2 7.3 7.4
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 6: Selected Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkalizing Agents	Decreased plasma salicylate levels.

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades des Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.1).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole

	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ

Low-dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND

	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decrease tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants	Increased bleeding

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Drug	Description
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

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Drug	Description
Heparin	Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Substance	Average Duration of Effect
Anti-thyroid drugs e.g., carbimazole, propylthiouracil	5 days
Natural or synthetic thyroid hormone e.g., thyroxine tri-iodothyronine	4 weeks 2 weeks
Iodine-containing medications e.g., amiodarone expectorants, vitamins	4 weeks 2 weeks
Topical iodide	1-9 months
X-ray contrast agents iodine-containing agents	Up to 1 year
Other drugs anticoagulants, antihistamines corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium	1 week 1 week 1 week 1-2 weeks 4 weeks

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule	Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)	Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
* Change relative to reference

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Antibiotics	ciprofloxacin, gentamicin, tobramycin, vancomycin, trimethoprim with sulfamethoxazole
Antineoplastics	melphalan
Antifungals	amphotericin B, ketoconazole
Anti-Inflammatory Drugs	azapropazon, colchicine, diclofenac, naproxen, sulindac
Gastrointestinal Agents	cimetidine, ranitidine
Immunosuppressives	tacrolimus
Other Drugs	fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

Table name:

Antibiotics	azithromycin, clarithromycin, erythromycin, quinupristin/dalfopristin
Antifungals	fluconazole, itraconazole, ketoconazole, voriconazole
Calcium Channel Blockers	diltiazem, nicardipine, verapamil
Glucocorticoids	methylprednisolone
Other Drugs	allopurinol, amiodarone, bromocriptine, colchicine, danazol, metoclopromide, imatinib, nefazodone, oral contraceptives

Table name:

Antibiotics	nafcillin, rifampin
Anticonvulsants	carbamazepine, oxcarbazepine, phenobarbital, phenytoin
Other Drugs/Dietary Supplements	bosentan, octreotide, orlistat, sulfinpyrazone, terbinafine, ticlopidine, St. John’s Wort

Table name:

AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-Containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport — but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
Lopinavir plus ritonavir	Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants: warfarin, rivaroxaban	↑ rivaroxaban	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants: lamotrigine, valproate	↓ lamotrigine ↓ or ↔ valproate	Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments [see Clinical Pharmacology (12.3)].
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone	↓ lopinavir ↑ glucocorticoids	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV-Protease Inhibitor: boceprevir	↓ lopinavir ↓ boceprevir ↓ ritonavir	It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see Clinical Pharmacology (12.3)].
HCV-Protease Inhibitor: telaprevir	↓ telaprevir ↔ lopinavir	It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected [see Clinical Pharmacology (12.3)].
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide	↑ glucocorticoids	Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics: methadone,* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 1. Selected Drugs that are Predicted to Alter the Plasma Concentration of Itraconazole or have their Plasma Concentration Altered by ItraconazoleThis list is not all-inclusive.
Drug Plasma Concentration Increased by Itraconazole
Antiarrhythmics	digoxin, dofetilideContraindicated with itraconazole based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.), quinidine, disopyramide
Anticonvulsants	carbamazepine
Antimycobacterials	rifabutin
Antineoplastics	busulfan, docetaxel, vinca alkaloids
Antipsychotics	pimozide
Benzodiazepines	alprazolam, diazepam, midazolam, For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. triazolam
Calcium Channel Blockers	dihydropyridines, (including felodipine and nisoldipine), verapamil
Gastrointestinal Motility Agents	cisapride
HMG CoA-Reductase Inhibitors	atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants	cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics	oral hypoglycemics
Protease Inhibitors	indinavir, ritonavir, saquinavir
Other	methadone, levacetylmethadol (levomethadyl), ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl

Decrease Plasma Concentration of Itraconazole
Anticonvulsants	carbamazepine, phenobarbital, phenytoin
Antimycobacterials	isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers	antacids, H₂-receptor antagonists, proton pump inhibitors
Non-nucleoside Reverse Transcriptase Inhibitors	nevirapine

Increase Plasma Concentration of Itraconazole
Macrolide Antibiotics	clarithromycin, erythromycin
Protease Inhibitors	indinavir, ritonavir

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Oral hypoglycemics	Coumarin-type anticoagulants	Phenytoin
Cyclosporine	Rifampin	Theophylline
Terfenadine	Cisapride	Astemizole
Rifabutin	Voriconazole	Tacrolimus
Short-acting benzodiazepines	Triazolam	Oral contraceptives
Pimozide	Hydrochlorothiazide	Alfentanil
Amitriptyline, nortriptyline	Amphotericin B	Azithromycin
Carbamazepine	Calcium channel blockers	Celecoxib
Cyclophosphamide	Fentanyl	Halofantrine
HMG-CoA reductase inhibitors	Losartan	Methadone
Non-steroidal anti-inflammatory drugs	Prednisone	Saquinavir
Sirolimus	Vinca alkaloids	Vitamin A
Zidovudine

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 8: Established Drug Interactions with VIDEX
Drug	Effect	Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
^a The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC.
ciprofloxacin	↓ ciprofloxacin concentration	Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin.
delavirdine	↓ delavirdine concentration	Administer VIDEX 1 hour after delavirdine.
ganciclovir	↑ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with VIDEX with caution. Monitor for didanosine-associated toxicity.
indinavir	↓ indinavir concentration	Administer VIDEX 1 hour after indinavir.
methadone	↓ didanosine concentration	Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after VIDEX.
tenofovir disoproxil fumarate	↑ didanosine concentration	A dose reduction of VIDEX to the following dosage once daily is recommended.^a 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) VIDEX and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 9: Predicted Drug Interactions with VIDEX
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase.
↓ Indicates decrease.
^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended [see Warnings and Precautions (5.1) ].
^b [See Warnings and Precautions (5.6) .]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution^b
Antacids containing magnesium or aluminum	↑ side effects associated with antacid components	Use caution with VIDEX Pediatric Powder for Oral Solution
Azole antifungals	↓ ketoconazole or itraconazole concentration	Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX.
Quinolone antibiotics (see also ciprofloxacin in Table 8)	↓ quinolone concentration	Consult package insert of the quinolone.
Tetracycline antibiotics	↓ antibiotic concentration	Consult package insert of the tetracycline.

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on ConcentrationIncrease = ↑; Decrease = ↓; No Effect = ↔	Clinical Comment
Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate)	↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake)	The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. ^, This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily. ↓ ketoconazole ^,	Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
H₂-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ rilpivirine ^, (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine ^, (famotidine taken 2 hours before rilpivirine)	The combination of COMPLERA and H₂-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H₂-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin	↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics: methadone	↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone (when used with tenofovir)	No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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NA – Not available/reported
Digoxin concentrations increased > 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased < 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Tolvaptan	30%	NA
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, quinine, rabeprazole,			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which were studies but reported no significant changes on digoxin exposure.			No additional actions are required.

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Drugs that Affect Renal Function	Caution should be exercised when combining digoxin with any drug that may cause significant deterioration in renal function (e.g., ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors) since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drug		Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).		Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic anti-depressants.		Pressor response increased.
Phenylephrine with ergot alkaloids.		Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.		Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.		Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.		Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.		Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.		Synergistic adrenergic response.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 7 Summary of AED Interactions with Trileptal
AED Coadministered	Dose of AED (mg/day)	Trileptal Dose (mg/day)	Influence of Trileptal on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 7. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg Q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole

	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ

Low-dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND

	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40% May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 8 Established and Other Potentially Significant Drug Interactions With Ganciclovir
Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and Valcyte each have the potential to cause neutropenia and anemia
Probenecid	↑ Ganciclovir	Patients taking probenecid and Valcyte should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Digoxin concentrations increased > 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril	58%	39%
Nitrendipine	57%	15%
Propafenone	35-85%	NA
Quinidine	100%	NA
Ranolazine	87%	88%
Ritonavir	NA	86%
Verapamil	50-75%	NA
Digoxin concentrations increased < 50%
Carvedilol	16%	14%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem	20%	NA
Nifedipine	45%	NA
Rabeprazole	29%	19%
Telmisartan	20%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anti-cancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St. John’s Wort, Sucralfate, Sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentrations changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Antiarrhythmics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Moricizine	Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinepherine	Can increase the risk of cardiac arrhythmias.
	Norepinephrine
	Dopamine
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers	Additive effects on AV node conduction can result in complete heart block.

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone) (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Interacting Drug	Interaction
Valproic acid	Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects (7.1)
Probenecid	Reduces renal clearance of doripenem, resulting in increased doripenem concentrations (7.2, 12.3)
Drugs metabolized by cytochrome P450 enzymes	Doripenem neither inhibits nor induces major cytochrome P450 enzymes (12.3)

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine gluronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine,	nifedipine
dietary ingestion	nizatidine
cefaclor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide
* Refer to PRECAUTIONS , Drug Interactions for information regarding table.

Table name:

Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

Table name:

Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 5: Results of Drug Interaction Studies with Stavudine: Effects of Coadministered Drug on Stavudine Plasma AUC and C_max Values
Drug	Stavudine Dosage	n^a	AUC of Stavudine (95% CI)	C_max of Stavudine (95% CI)
↑ indicates increase ↔ indicates no change, or mean increase or decrease of greater then 10%. ^a HIV-infected patients.
Didanosine, 100 mg q12h for 4 days	40 mg q12h for 4 days	10	↔	↑17%
Lamivudine, 150 mg single dose	40 mg single dose	18	↔ (92.7-100.6%)	↑12% (100.3-126.1%)
Nelfinavir, 750 mg q8h for 56 days	30 to 40 mg q12h for 56 days	8	↔	↔

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Table 6: Results of Drug Interaction Studies with Stavudine: Effects of Stavudine on Coadministered Drug Plasma AUC and C_max Values
Drug	StavudineDosage	n^a	AUC of Coadministered Drug (95% CI)	C_max of Coadministered Drug (95% CI)
↔ indicates no change, or mean increase or decrease of greater then 10%. ^a HIV-infected patients.
Didanosine, 100 mg q12h for 4 days	40 mg q12h for 4 days	10	↔	↔
Lamivudine, 150 mg single dose	40 mg single dose	18	↔ (90.5-107.6%)	↔ (87.1-110.6%)
Nelfinavir, 750 mg q8h for 56 days	30 to 40 mg q12h for 56 days	8	↔	↔

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Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects ** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUCτ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz** (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see CLINICAL PHARMACOLOGY (12.3)]
Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg QD) Non-Steroidal Anti-Inflammatory Drug *** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUCτ)	Recommendations for Drug DosageAdjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz** (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministeredwith efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on	Contraindicated because of significant reduction of voriconazole C_max and AUCτ
	Ritonavir C_max or AUCτ

Low-dose Ritonavir (100 mg q12h)**	Slight Decrease in Ritonavir C_max and AUCτ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUCτ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac(CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole*(CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors	In Vivo Studies Showed No Significant	No dosage adjustment for indinavirwhen coadministered with voriconazole tablets
(CYP3A4 Inhibition)	Effects on Indinavir Exposure
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for Magnitude of Interaction.

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Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_{max SS} (Peak plasma concentration)	AUC_SS(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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AED Coadministered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine

Rifampin Theophylline Terfenadine Cisapride

Astemizole Rifabutin Tacrolimus Short-acting benzodiazepines

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	CmaxSS (Peak plasma concentration)	AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety ( Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference )		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Table 7 Summary of AED Interactions with Trileptal
AED Coadministered	Dose of AED (mg/day)	Trileptal Dose (mg/day)	Influence of Trileptal on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Interacting Drug	Interaction
Multivalent cation - containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) (Tables 12 and 13) for magnitude of interaction]
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV Antiviral Agents: Reverse Transcriptase Inhibitors
Delavirdine	↑ nelfinavir (C_min) ↓ delavirdine	Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established.
Nevirapine	↓ nelfinavir (C_min)	Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established.
Didanosine	↔ nelfinavir	There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
HIV Antiviral Agents: Protease Inhibitors
Indinavir	↑ nelfinavir ↑ indinavir	Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
Ritonavir	↑ nelfinavir ↔ ritonavir	Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established.
Saquinavir	↑ nelfinavir ↑ saquinavir	Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
ANTICOAGULANT
Warfarin	Warfarin	Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
ANTICONVULSANTS
Carbamazepine Phenobarbital Phenytoin	↓ nelfinavir ↓ phenytoin	Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
ANTIDEPRESSANT
Trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIGOUT
Colchicine	↑ colchicines	Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity. Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
Rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)	It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
ENDOTHELIN RECEPTOR ANTAGONIST
Bosentan	↑ bosentan	Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin Rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day.
IMMUNOSUPPRESSANTS
Cyclosporine Tacrolimus Sirolimus	↑ immuno-suppressants ↑ nelfinavir	Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir.
INHALED BETA AGONIST
Salmeterol	↑ salmeterol	Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INHALED/NASAL STEROID
Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
MACROLIDE ANTIBIOTIC
Azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
NARCOTIC ANALGESIC
Methadone	↓ methadone	Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT.
HORMONAL CONTRACEPTIVES
Ethinyl estradiol Norethindrone	↓ ethinyl estradiol ↓ norethindrone	Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered.
PDE5 INHIBITORS
Sildenafil Vardenafil Tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.
PROTON PUMP INHIBITORS
Omeprazole	↓ nelfinavir	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and torsade de pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine gluronidation). ?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin	melphalan	azapropazon	cimetidine
gentamicin		colchicine	ranitidine
tobramycin	Antifungals	diclofenac
vancomycin	amphotericin B	naproxen	Immunosuppressives
trimethoprim with sulfamethoxazole	ketoconazole	sulindac	tacrolimus

			Other Drugs
			fibric acid derivatives
			(e.g.,bezafibrate, fenofibrate) methotrexate

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/		colchicine
		dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		St. John's Wort
		terbinafine
		ticlopidine

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin	Contraindicated with lovastatin
Gemfibrozil, cyclosporine	Avoid with lovastatin
Danazol, diltiazem, dronedarone, verapamil	Do not exceed 20 mg lovastatin daily
Amiodarone	Do not exceed 40 mg lovastatin daily
Grapefruit juice	Avoid grapefruit juice

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects ** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUCτ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz** (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

Table name:

Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see CLINICAL PHARMACOLOGY (12.3)]
Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg QD) Non-Steroidal Anti-Inflammatory Drug *** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUCτ)	Recommendations for Drug DosageAdjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz** (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministeredwith efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on	Contraindicated because of significant reduction of voriconazole C_max and AUCτ
	Ritonavir C_max or AUCτ

Low-dose Ritonavir (100 mg q12h)**	Slight Decrease in Ritonavir C_max and AUCτ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUCτ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors	In Vivo Studies Showed No Significant	No dosage adjustment for indinavir when coadministered with voriconazole tablets
(CYP3A4 Inhibition)	Effects on Indinavir Exposure
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

Table name:

Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name	Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,^a rifampin^a	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort (Hypericum perforatum)	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

Table name: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be reduced by 75%.

Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Delavirdine or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitor
Didanosine^a	↓Delavirdine ↓Didanosine	Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors
NNRTI	↔Delavirdine ↑NNRTI	Combining NNRTIs has not been shown to be beneficial. RESCRIPTOR should not be coadministered with another NNRTI.
HIV-Antiviral Agents: Protease Inhibitors
Indinavir^a	↑Indinavir	A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir	↑Lopinavir ↑Ritonavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavir^a	↑Nelfinavir ↓Delavirdine	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established (see CLINICAL PHARMACOLOGY: Tables 1 and 2).
Ritonavir	↑Ritonavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavir^a	↑Saquinavir	A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
HIV-Antiviral Agents: CCR5 Inhibitor
Maraviroc	↑Maraviroc	Concomitant use of RESCRIPTOR and maraviroc has not been studied. However, RESCRIPTOR is a potent CYP3A4 inhibitor and the maraviroc dose should be reduced during coadministration. Refer to the full prescribing information for maraviroc (SELZENTRY) for dosing recommendations.
Other Agents
Acid blockers: Antacids^a	↓Delavirdine	Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine	↓Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole	↓Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines	↑Amphetamines	Use with caution.
Antidepressant: Trazodone	↑Trazodone	Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiarrhythmics: Bepridil	↑Antiarrhythmics	Use with caution. Increased bepridil exposure may be associated with life‑threatening reactions such as cardiac arrhythmias.
Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone		Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin	↑Warfarin	It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycin^a	↑Clarithromycin	When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function:
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil	↑Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Delavirdine	Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil	↑Sildenafil	Sildenafil should not exceed a maximum single dose of 25 mg in a 48‑hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin	↑Atorvastatin ↑Cerivastatin ↑Fluvastatin	Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone	↑Fluticasone	Concomitant use of fluticasone and RESCRIPTOR may increase plasma concentrations of fluticasone. Use with caution. Consider alternatives to fluticasone, particularly for long-term use.
Narcotic analgesic: Methadone	↑Methadone	Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol	↑Ethinyl estradiol	Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreated when the tablet or oral solution formulation is taken with 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Anti-diabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction [See Clinical Pharmacology (12.3) (Tables 6 and 7) for Magnitude of Interaction.]
Concomitant Drug Class: Drug Name	Effect on concentration of INCIVEK or Concomitant Drug	Clinical Comment
The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK.
ANTIARRHYTHMICS
lidocaine (systemic), amiodarone, bepridil, flecainide, propafenone, quinidine	↑ antiarrhythmics	Co-administration with telaprevir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir.
digoxinThese interactions have been studied. See Clinical Pharmacology (12.3), Tables 6 and 7.	↑ digoxin	Concentrations of digoxin were increased when co-administered with telaprevir. The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
ANTIBACTERIALS
clarithromycin erythromycin telithromycin	↑ telaprevir ↑ antibacterials	Concentrations of both telaprevir and the antibacterial may be increased during co-administration. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. QT interval prolongation and Torsade de Pointes have been reported with clarithromycin and erythromycin. QT interval prolongation has been reported with telithromycin.
ANTICOAGULANT
warfarin	↑ or ↓ warfarin	Concentrations of warfarin may be altered when co-administered with telaprevir. The international normalized ratio (INR) should be monitored when warfarin is co-administered with telaprevir.
ANTICONVULSANTS
carbamazepine phenobarbital phenytoin	↓ telaprevir ↑ carbamazepine ↑ or ↓ phenytoin ↑ or ↓ phenobarbital	Concentrations of the anticonvulsant may be altered and concentrations of telaprevir may be decreased. Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. Telaprevir may be less effective in patients taking these agents concomitantly. Clinical or laboratory monitoring of carbamazepine, phenobarbital, and phenytoin concentrations and dose titration are recommended to achieve the desired clinical response.
ANTIDEPRESSANTS
escitalopram	↔ telaprevir ↓ escitalopram	Concentrations of escitalopram were decreased when co-administered with telaprevir. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with telaprevir.
trazodone	↑ trazodone	Concomitant use of trazodone and telaprevir may increase plasma concentrations of trazodone which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone is used with telaprevir, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIFUNGALS
ketoconazole itraconazole posaconazole voriconazole	↑ ketoconazole ↑ telaprevir ↑ itraconazole ↑ posaconazole ↑ or ↓ voriconazole	Ketoconazole increases the plasma concentrations of telaprevir. Concomitant systemic use of itraconazole or posaconazole with telaprevir may increase plasma concentration of telaprevir. Plasma concentrations of itraconazole, ketoconazole, or posaconazole may be increased in the presence of telaprevir. When co-administration is required, high doses of itraconazole or ketoconazole (greater than 200 mg/day) are not recommended.
		Caution is warranted and clinical monitoring is recommended for itraconazole, posaconazole and voriconazole.
		QT interval prolongation and Torsade de Pointes have been reported with voriconazole and posaconazole. QT interval prolongation has been reported with ketoconazole. Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction with telaprevir. Voriconazole should not be administered to patients receiving telaprevir unless an assessment of the benefit/risk ratio justifies its use.
ANTI GOUT
colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with telaprevir, due to the risk of colchicine toxicity. A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function. Treatment of gout flares: co-administration of colchicine in patients on telaprevir: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. If used for prophylaxis of gout flares: co-administration of colchicine in patients on telaprevir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): co-administration of colchicine in patients on telaprevir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
rifabutin	↓ telaprevir ↑ rifabutin	Concentrations of telaprevir may be decreased, while rifabutin concentrations may be increased during co-administration. Telaprevir may be less effective due to decreased concentrations. The concomitant use of rifabutin and telaprevir is not recommended.
BENZODIAZEPINES
alprazolam	↑ alprazolam	Concomitant use of alprazolam and telaprevir increases exposure to alprazolam. Clinical monitoring is warranted.
parenterally administered midazolam	↑ midazolam	Concomitant use of parenterally administered midazolam with telaprevir increased exposure to midazolam. Co-administration should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
		Co-administration of oral midazolam with telaprevir is contraindicated.
zolpidem (non-benzodiazepine sedative)	↓ zolpidem	Exposure to zolpidem was decreased when co-administered with telaprevir. Clinical monitoring and dose titration of zolpidem is recommended to achieve the desired clinical response.
CALCIUM CHANNEL BLOCKERS
amlodipine	↑ amlodipine	Exposure to amlodipine was increased when co-administered with telaprevir. Caution should be used and dose reduction for amlodipine should be considered. Clinical monitoring is recommended.
diltiazem felodipine nicardipine nifedipine nisoldipine verapamil	↑calcium channel blockers	Concentrations of other calcium channel blockers may be increased when telaprevir is co-administered. Caution is warranted and clinical monitoring of patients is recommended.
CORTICOSTEROIDS
Systemic prednisone methylprednisolone	↑ prednisone ↑ methylprednisolone	Systemic corticosteroids such as prednisone and methylprednisolone are CYP3A substrates. Since telaprevir is a strong CYP3A inhibitor, plasma concentrations of these corticosteroids can be increased significantly. Co-administration of systemic corticosteroids and telaprevir is not recommended [see Warnings and Precautions (5.1) ].
Systemic dexamethasone	↓ telaprevir	Systemic dexamethasone induces CYP3A and can thereby decrease telaprevir plasma concentrations. This may result in loss of therapeutic effect of telaprevir. Therefore this combination should be used with caution or alternatives should be considered.
Inhaled/Nasal fluticasone budesonide	↑fluticasone ↑ budesonide	Concomitant use of inhaled fluticasone or budesonide and telaprevir may increase plasma concentrations of fluticasone or budesonide resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
ENDOTHELIN RECEPTOR ANTAGONIST
bosentan	↑ bosentan	Concentrations of bosentan may be increased when co-administered with telaprevir. Caution is warranted and clinical monitoring is recommended.
HIV-ANTIVIRAL AGENTS: HIV-PROTEASE INHIBITORS (PIs)
atazanavir/ritonavir	↓ telaprevir ↑ atazanavir	Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
darunavir/ritonavir	↓ telaprevir ↓ darunavir	Concomitant administration of telaprevir and darunavir/ritonavir resulted in reduced steady-state exposures to telaprevir and darunavir. It is not recommended to co-administer darunavir/ritonavir and telaprevir.
fosamprenavir/ritonavir	↓ telaprevir ↓ fosamprenavir	Concomitant administration of telaprevir and fosamprenavir/ritonavir resulted in reduced steady-state exposures to telaprevir and amprenavir. It is not recommended to co-administer fosamprenavir/ritonavir and telaprevir.
lopinavir/ritonavir	↓ telaprevir ↔ lopinavir	Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced steady-state telaprevir exposure, while the steady-state exposure to lopinavir was not affected. It is not recommended to co-administer lopinavir/ritonavir and telaprevir.
HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
efavirenz	↓ telaprevir ↓ efavirenz	Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
tenofovir disoproxil fumarate	↔ telaprevir ↑ tenofovir	Concomitant administration of telaprevir and tenofovir disoproxil fumarate resulted in increased tenofovir exposure. Increased clinical and laboratory monitoring are warranted. Tenofovir disoproxil fumarate should be discontinued in patients who develop tenofovir-associated toxicities.
HMG-CoA REDUCTASE INHIBITORS
atorvastatin fluvastatin pitavastatin pravastatin rosuvastatin	↑ statin	Plasma concentrations of atorvastatin are markedly increased when co-administered with telaprevir. Avoid concomitant administration of telaprevir and atorvastatin. For fluvastatin, pitavastatin, pravastatin, and rosuvastatin, caution is warranted and clinical monitoring is recommended. Refer to Contraindications (4) for HMG-CoA reductase inhibitors (lovastatin, simvastatin) that are contraindicated with INCIVEK.
HORMONAL CONTRACEPTIVES/ESTROGEN
ethinyl estradiol norethindrone	↓ ethinyl estradiol ↔ norethindrone	Exposure to ethinyl estradiol was decreased when co-administered with telaprevir. Two effective non-hormonal methods of contraception should be used during treatment with telaprevir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Refer also to Contraindications (4) , Warnings and Precautions (5.3) , Use in Specific Populations (8.1) , and Patient Counseling Information (17.2) .
IMMUNOSUPPRESSANTS
cyclosporine sirolimus tacrolimus	↑ cyclosporine ↑ sirolimus ↑ tacrolimus	Plasma concentrations of cyclosporine and tacrolimus are markedly increased when co-administered with telaprevir. Plasma concentration of sirolimus may be increased when co-administered with telaprevir, though this has not been studied. Significant dose reductions and prolongation of the dosing interval of the immunosuppressant to achieve the desired blood levels should be anticipated. Close monitoring of the immunosuppressant blood levels, and frequent assessments of renal function and immunosuppressant-related side effects are recommended when co-administered with telaprevir. Tacrolimus may prolong the QT interval. The use of telaprevir in organ transplant patients has not been studied.
INHALED BETA AGONIST
salmeterol	↑ salmeterol	Concentrations of salmeterol may be increased when co-administered with telaprevir. Concurrent administration of salmeterol and telaprevir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INSULIN SECRETAGOGUES
repaglinide	↑ repaglinide	Caution is warranted and clinical monitoring is recommended.
NARCOTIC ANALGESIC
methadone	↓ R-methadone	Concentrations of methadone were reduced when co-administered with telaprevir. No adjustment of methadone dose is required when initiating co-administration of telaprevir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
PDE5 INHIBITORS
sildenafil tadalafil vardenafil	↑ PDE5 inhibitors	Concentrations of PDE5 inhibitors may be increased when co-administered with telaprevir. For the treatment of erectile dysfunction, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE5 inhibitor-associated adverse events. QT interval prolongation has been reported with vardenafil. Caution is warranted and clinical monitoring is recommended. Co-administration of sildenafil or tadalafil and telaprevir in the treatment of pulmonary arterial hypertension is contraindicated [see Contraindications (4) ].

Table name:

Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

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Table 3
SUPRANE (desflurane, USP) MAC with Fentanyl or Midazolam Mean ± SD (percent reduction)
Dose	18-30 years	31-65 years
No fentanyl	6.4 ± 0.0	6.3 ± 0.4
3 µg/kg fentanyl	3.5 ± 1.9 (46%)	3.1 ± 0.6 (51%)
6 µg/kg fentanyl	3.0 ± 1.2 (53%)	2.3 ± 1.0 (64%)
No midazolam	6.9 ± 0.1	5.9 ± 0.6
25 µg/kg midazolam	-	4.9 ± 0.9 (16%)
50 µg/kg midazolam	-	4.9 ± 0.5 (17%)

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Table 4
Dosage of Muscle Relaxant Causing 95% Depression in Neuromuscular Blockade
Desflurane Concentration	Mean ED₉₅ (µg/kg)
Desflurane Concentration	Pancuronium	Atracurium	Succinylcholine	Vecuronium
0.65 MAC 60% N₂O/O₂	26	123	-	-
1.25 MAC 60% N₂O/O₂	18	91	-	-
1.25 MAC O₂	22	120	362	19

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 9: Established Drug Interactions with Didanosine
Drug	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a The dosing recommendation for coadministration of didanosine delayed-release capsules and tenofovir disoproxil fumarate with respect to meal consumption differs from that of didanosine. See the complete prescribing information for didanosine delayed-release capsules.
ciprofloxacin	↓ ciprofloxacin concentration	Administer didanosine at least 2 hours after or 6 hours before ciprofloxacin.
delavirdine	↓ delavirdine concentration	Administer didanosine 1 hour after delavirdine.
ganciclovir	↓ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
indinavir	↓ indinavir concentration	Administer didanosine 1 hour after indinavir.
methadone	↓ didanosine concentration	Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load.
nelfinavir	↓ No interacion 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine.
tenofovir disoproxil fumarate	↓ didanosine concentration	A dose reduction of didanosine to the following dosage once daily is recommended.^a 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Didanosine and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, didanosine should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 10: Predicted Drug Interactions with Didanosine
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)]. ^b [See Warnings and Precautions (5.6).]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution^b
Antacids containing magnesium or aluminum	↑ side effects associated with antacid components	Use caution with didanosine tablets for oral suspension and didanosine pediatric powder for oral solution
Azole antifungals	↓ ketoconazole or Itraconazole concentration	Administer drugs such as ketoconazole or itraconazole at least 2 hours before didanosine.
Quinolone antibiotics (see also ciprofloxacin in Table 9)	↓ quinolone concentration	Consult package insert of the quinolone.
Tetracycline antibiotics	↓ antibiotic concentration	Consult package insert of the tetracycline.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUCτ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin, and Rifabutin(CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz** (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h) (CYP450 Induction) Low dose Ritonavir (100 mg q12h) (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives**containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of vorconazole and fluconazole Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs***(CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

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Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC _τ )	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz**(CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazolemaintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h) (CYP3A4 Inhibition) Low dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate associated adverse events may be necessary [see Drug Interactions (7)]
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [see Drug Interactions (7)]

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NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.

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Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and	finasteride	norfloxacin
inhaled	hydrocortisone	ofloxacin
amoxicillin	isoflurane	omeprazole
ampicillin, with or without	isoniazid	prednisone, prednisolone
sulbactam	isradipine	ranitidine
atenolol	influenza vaccine	rifabutin
azithromycin	ketoconazole	roxithromycin
caffeine, dietary ingestion	lomefloxacin	sorbitol
cefaclor	mebendazole	(purgative doses do not
co-trimoxazole	medroxyprogesterone	inhibit theophylline
(trimethoprim and	methylprednisolone	absorption)
sulfamethoxazole)	metronidazole	sucralfate
diltiazem	metoprolol	terbutaline,systemic
dirithromycin	nadolol	terfenadine
enflurane	nifedipine	tetracycline
famotidine	nizatidine	tocainide
felodipine

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine gluronidation). ?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole

	% Change from Plavix (300 mg/75 mg) alone
Plavix plus	C_max (ng/mL)		AUC		Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
	Day 1	Day 5	Day 1	Day 5AUC at Day 5 is AUC_0–24	Day 1	Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg	↓46%	↓42%	↓45%	↓40%	↓39%	↓21%
Pantoprazole 80 mg	↓24%	↓28%	↓20%	↓14%	↓15%	↓11%

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Table 5 Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration with Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole(400 mg once daily)	+135%	+164%

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Table 2: Drugs That May Decrease T₄ Absorption (Hypothyroidism)
Drug or Drug Class	Effect
Potential impact: Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Calcium Carbonate Ferrous Sulfate	Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents.
Orlistat	Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Bile Acid Sequestrants -Colesevelam -Cholestyramine -Colestipol Ion Exchange Resins -Kayexalate -Sevelamer	Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine at least 4 hours prior to these drugs or monitor thyrotropin-stimulating hormone (TSH) levels.
Other drugs: Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone

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Table 3: Drugs That May Alter T₄ and Triiodothyronine (T₃) Serum Transport Without Effecting Free Thyroxine (FT₄) Concentration (Euthyroidism)
Drugs That May Increase Serum Thyroxine-Binding Globulin (TBG) Concentration	Drugs That May Decrease Serum TBG Concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs That May Cause Protein-Binding Site Displacement
Potential impact: Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations, and patients are likely clinically euthyroid.
Salicylates (> 2 g/day)	Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total T₄ levels may decrease by as much as 30%.
Other drugs: Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates - Phenylbutazone

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Table 4: Drugs That May Alter Hepatic Metabolism of T₄ (Hypothyroidism)
Drug or Drug Class	Effect
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements.
Carbamazepine Hydantoins	Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and FT4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Close monitoring of thyroid hormone parameters is recommended.
Other drugs: Phenobarbital Rifampin

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Table 5: Drugs That May Decrease Conversion of T₄ to T₃
Drug or Drug Class	Effect
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased.
Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day)	In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state.
Glucocorticoids (e.g., Dexamethasone ≥ 4 mg/day)	Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (See above).
Other: Amiodarone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	CmaxSS (Peak plasma concentration)	AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Drug		Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).		Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic anti-depressants.		Pressor response increased.
Phenylephrine with ergot alkaloids.		Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.		Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.		Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.		Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.		Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.		Synergistic adrenergic response.

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Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with VYTORIN
Verapamil, diltiazem	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2. Drug Interactions with PRIFTIN: Dosage Adjustment may be Necessary
Drug Class	Examples of Drugs Within Class
Antiarrhythmics	Disopyramide, mexiletine, quinidine, tocainide
Antibiotics	Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin)
Oral Anticoagulants	Warfarin
Anticonvulsants	Phenytoin
Antimalarials	Quinine
Azole Antifungals	Fluconazole, itraconazole, ketoconazole
Antipsychotics	Haloperidol
Barbiturates	Phenobarbital
Benzodiazepines	Diazepam
Beta-Blockers	Propanolol
Calcium Channel Blockers	Diltiazem, nifedipine, verapamil
Cardiac Glycoside Preparations	Digoxin
Corticosteroids	Prednisone
Fibrates	Clofibrate
Oral Hypoglycemics	Sulfonylureas (e.g., glyburide, glipizide)
Hormonal Contraceptives/ Progestins	Ethinyl estradiol, levonorgestrel
Immunosuppressants	Cyclosporine, tacrolimus
Methylxanthines	Theophylline
Narcotic analgesics	Methadone
Phophodiesterase-5 (PDE-5) Inhibitors	Sildenafil
Thyroid preparations	Levothyroxine
Tricyclic antidepressants	Amitriptyline, nortriptyline

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration		Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen		Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 4. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 3. Selected Drugs that altered or are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by ONMELThis list is not all-inclusive.
Drug plasma concentration increased by itraconazole
Antiarrhythmics	digoxin, dofetilide, quinidine, disopyramide
Anticonvulsants	carbamazepine
Anti-HIV Agents	indinavir, ritonavir, saquinavir, maraviroc
Antineoplastics	busulfan, docetaxel, vinca alkaloids
Antipsychotics	pimozide
Benzodiazepines	alprazolam, diazepam, midazolam,For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. triazolam
Calcium Channel Blockers	dihydropyridines (including nisoldipine and felodipine), verapamil
Gastrointestinal Motility Agents	cisapride
HMG CoA-Reductase Inhibitors	atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants	Cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics	oral hypoglycemics (repaglinide)
Opiate Analgesics	fentanyl, levacetylmethadol (levomethadyl), methadone
Polyene Antifungals	amphotericin B
Other	ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide

Decrease plasma concentration of itraconazole
Anticonvulsants	carbamazepine, phenobarbital, phenytoin
Anti-HIV Agents	nevirapine, efavirenz
Antimycobacterials	isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers	antacids, H₂-receptor antagonists, proton pump inhibitors

Increase plasma concentration of itraconazole
Macrolide Antibiotics	clarithromycin, erythromycin
Anti-HIV Agents	indinavir, ritonavir

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Table 4. Selected Drugs that are contraindicated for use with itraconazoleThis list is not all-inclusive.
Antipsychotics	pimozide
Antiarrhythmics	dofetilide, quinidine
Benzodiazepines	oral midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers	Nisoldipine, felodipine
Ergot Alkaloids	dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine)
Gastrointestinal Motility Agents	cisapride
HMG CoA-Reductase Inhibitors	lovastatin, simvastatin
Opiate Analgesics	levacetylmethadol (levomethadyl), methadone

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.

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Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
^a Should be administered at least 4 hours prior to WELCHOL
^b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
^c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
Drugs with a known interaction with colesevelam	Cyclosporine^c, glyburide^a, levothyroxine^a, and oral contraceptives containing ethinyl estradiol and norethindrone^a
Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL	phenytoin^a, warfarin^b
Drugs that do not interact with colesevelam based on in vitro or in vivo testing	cephalexin, ciprofloxacin, digoxin, warfarin^b fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T , and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule	Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio * )	Risperidone Dose Recommendation
Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 mg or 3 mg twice daily	1.4	1.5	Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	--	Reevaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	--
	40 mg/day -	4 mg/day	1.8	--
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and	finasteride	norfloxacin
inhaled	hydrocortisone	ofloxacin
amoxicillin	isoflurane	omeprazole
ampicillin, with or without	isoniazid	prednisone, prednisolone
sulbactam	isradipine	ranitidine
atenolol	influenza vaccine	rifabutin
azithromycin	ketoconazole	roxithromycin
caffeine, dietary ingestion	lomefloxacin	sorbitol
cefaclor	mebendazole	(purgative doses do not
co-trimoxazole	medroxyprogesterone	inhibit theophylline
(trimethoprim and	methylprednisolone	absorption)
sulfamethoxazole)	metronidazole	sucralfate
diltiazem	metoprolol	terbutaline,systemic
dirithromycin	nadolol	terfenadine
enflurane	nifedipine	tetracycline
famotidine	nizatidine	tocainide
felodipine

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)